Name Aliases Binding partner Physiology / Oncology References

AJAP1 Adherens junction associated 1, ? PHY : Expressed in uterus and . [1] http://www.uniprot.org/uniprot/Q9UKB5. [2] SHREW1 Plays a role in and migration. McDonald JM, Biol Ther 2006, 5:300-4 Forms a complex with CDH1 and beta-catenin at adherens junctions [1]

ONC : Frequently deleted in oligodendrogliomas, functions to inhibit cell adhesion and migration [2] ALCAM Activated leukocyte cell adhesion CD6 PHY : Adhesion of activated leukocytes and [1] Ofori-Acquah SF, Transl Res 2008, 151:122- molecule, CD166, MEMD (melanoma neurons 8. [2] van Kilsdonk JW, Cancer Res 2008, metastasis clone D) 68:3671-9 ONC : Expressed by different tumor types including melanoma; mediates cancer/ melanoma invasiveness [1,2] AMICA1 Adhesion molecule interacting with CXADR PHY : Expression is restricted to the [1] http://www.uniprot.org/uniprot/Q86YT9. [2] CXADR antigen 1, JAML (junctional hematopoietic tissues with the exception of Moog-Lutz C, Blood 2003, 102:3371-8 adhesion molecule-like) liver. May function in transmigration of leukocytes through epithelial and endothelial tissues. Mediates adhesive interactions with CXADR, a protein of the junctional complex of epithelial cells [1]

ONC : Enhances myeloid leukemia cell adhesion to endothelial cells [2] AMIGO1 Amphoterin-induced and open AMIGO PHY : May be involved in fasciculation as well [1] http://www.uniprot.org/uniprot/Q86WK6 reading frame 1, Alivin-2 as myelination of developing neural axons. May have a role in regeneration as well as neural plasticity in the adult nervous system. May mediate homophilic as well as heterophilic cell-cell interaction and contribute to through its intracellular domain [1]

ONC : - AMIGO2 Amphoterin-induced gene and open AMIGO PHY : Highest levels in breast, ovary, cervix, [1] http://www.uniprot.org/uniprot/Q86SJ2. [2] reading frame 2, DEGA (Differentially and uterus. May mediate homophilic as well Rabenau KE, 2004, 23:5056-67 expressed in gastric adenocarcinomas) as heterophilic cell-cell interaction with

MMMP Biomap #87 Page 1 AMIGO1 or AMIGO3. May contribute to signal transduction through its intracellular domain [1]

ONC : High expression in 45% of gastric adenocarcinomas; stable expression of an antisense construct in a gastric adenocarcinoma cell line leads to increased ploidy, chromosomal instability, decreased cell adhesion/ migration and nearly complete abrogation of tumorigenicity in nude mice [2] AMIGO3 Amphoterin-induced gene and open AMIGO PHY : May mediate heterophilic cell-cell [1] http://www.uniprot.org/uniprot/Q86WK7 reading frame 3 interaction. May contribute to signal transduction through its intracellular domain [1]

ONC : - BCAM Basal , CD239, Laminins (?) PHY : Associated with basal layer of epithelial [1] Kikkawa Y, Exp Cell Res 2008, 314:2579-90 Lutheran blood group antigen and endothelial cells

ONC : Mediates adhesion of hepatocellular carcinoma (HCC) cells to laminin alpha 5 [1] CADM1 Cell adhesion molecule 1, TSLC1 (tumor CADM1 PHY : Calcium-independent homophilic and [1] Murakami Y, Cancer Sci 2005, 96:543-52. [2] suppressor in cancer), IGSF4, CADM3 heterophilic cell-cell adhesion Nowacki S, Oncogene 2008, 27:3329-38. [3] SYNCAM1 PVRL3 Kikuchi S, Cancer 2006, 106:1751-8 ONC : Considered a [1], especially for neuroblastoma [2] and lung cancer [3] CADM2 Cell adhesion molecule 2, NECL3, ? PHY : ? [1] http://www.uniprot.org/uniprot/Q8N3J6 SYNCAM2 ONC : - CADM3 Cell adhesion molecule 3, IGSF4B, CADM3 PHY : Calcium-independent homophilic and [1] Fukuhara H, Oncogene 2001, 20:5401-7 TSLL1 (TSLC1-like 1), NECL1, IGSF4 heterophilic cell-cell adhesion activity SYNCAM3 PVRL1 PVRL3 ONC : Possibly involved in cancer biology (CADM1 homologous) [1] CADM4 Cell adhesion molecule 4, IGSF4C, ? PHY : Calcium- and magnesium-independent [1] Fukuhara H, Oncogene 2001, 20:5401-7 TSLL2 (TSLC1-like 2), NECL4, cell-cell adhesion activity SYNCAM4 ONC : Possibly involved in cancer biology MMMP Biomap #87 Page 2 (CADM1 homologous) [1] CD2 CD2 antigen p50, LFA-2, LFA-3 receptor, LFA-3 PHY : CD2 interacts with lymphocyte function- [1] http://www.uniprot.org/uniprot/P06729. [2] rosette receptor, T-cell surface antigen CD48 associated antigen (LFA-3) and CD48 to Perea G, Leuk Res 2005, 29:1109-16 T11/Leu-5 mediate adhesion between T-cells and other cell types. CD2 is implicated in the triggering of T-cells, the cytoplasmic domain is implicated in the signaling function

ONC : CD2 (and CD36) expression has an adverse prognostic impact in adult de novo acute myeloid leukemia (AML) patients [2] CD4 CD4 antigen p55, T-cell surface antigen MHC class II PHY : Identifies helper T cells (HTL) and [1] http://www.uniprot.org/uniprot/P01730 T4/Leu-3 suppressor/ regulatory T cells (Treg) that interact with MHC class II bearing targets. Singaling and adhesion coreceptor in class II restricted antigen-induced T cell activation. Primary receptor for HIV virus [1]

ONC : - CD6 Tp120 CD166 PHY : Expressed by thymocytes, mature T- [1] http://www.uniprot.org/uniprot/P30203 cells, a subset of B-cells known as B-1 cells, and by some cells in the brain. After T-cell activation, becomes phosphorylated on Ser, Thr and Tyr residues [1]

ONC : - CD8a CD8 alpha (p32), T-lymphocyte MHC class I PHY : Identifies cytotoxic T cells (CTL) and [1] Smith TR, Trends Immunol 2008, 29:337-42. differentiation antigen T8/Leu-2 suppressor/ regulatory T cells (Treg) that [2] http://www.uniprot.org/uniprot/P01732 interact with MHC class I bearing targets. Signaling and adhesion coreceptor in class II restricted antigen-induced T cell activation. In general heterodimer of an alpha and a beta chain [2]

ONC : - CD8b CD8 beta (p37), T-cell surface MHC class I PHY : Identifies cytotoxic T cells (CTL) and [1] Smith TR, Trends Immunol 2008, 29:337-42. CD8 beta chain suppressor/ regulatory T cells (Treg) that [2] http://www.uniprot.org/uniprot/P10966 interact with MHC class I bearing targets. Signaling and adhesion coreceptor in class II restricted antigen-induced T cell activation. In general heterodimer of an alpha and a beta MMMP Biomap #87 Page 3 chain [2]

ONC : - CD9 Tetraspanin-29, Leukocyte antigen MIC3 ? PHY : Involved in platelet activation and [1] http://www.uniprot.org/uniprot/P21926. [2] aggregation. Regulates paranodal junction Ikeyama S, J Exp Med 1993, 177:1231-7. [3] formation. Required for gamete fusion. Miyake M, Oncogene 2000, 19:5221-6. [4] Involved in cell adhesion and motility. Nakazawa Y, Blood 2008, 112:1730-9. [5] De Bruyne E, Clin Cancer Res 2008, 14:2918-26. Expressed by a variety of hematopoietic and [6] Longo N, Blood 2001, 98:3717-26. [7] Hong epithelial cells [1]. CD9 (and CD81) associate IK, Exp Mol Med 2005, 37:230-9. [8] Hemler with phosphatidyl inositol 4-kinase (PI4K), ME, Nat Rev Mol Cell Biol 2005, 6:801-11 which locally produces phosphoinositides (such as phosphatidylinositol-4,5- bisphosphate; this causes the recruitment and activation of SHC (SRC-homology-2-domain- containing transforming protein): subsequent RAS-mediated activation of ERK or p38MAPK or JNK pathways leads to proliferation or , respectively [8]

ONC : Suppresses cell motility and in vivo metastasis of mouse melanoma [2,3]. CD9 may act as a metastasis suppressor, at least in part, by neutralizing Aggrus-mediated platelet aggregation [4]. In multiple myeloma, CD9 is epigenetically silenced during disease progression and correlates with survival [5]. However, anti-CD9 inhibit transendothelial migration of melanoma cells [6]; plus, CD9 induces MMP-2 expression by activating c- Jun through p38 MAPK and JNK signaling pathways in melanoma cells [7] CD33 CD33 antigen (gp67), SIGLEC3 (Sialic Sialic acid containing PHY : Putative adhesion molecule of [1] http://www.uniprot.org/uniprot/P20138. [2] acid-binding Ig-like 3), myelomonocytic-derived cells that mediates Stasi R, Expert Opin Biol Ther 2008, 8:527-40 sialic-acid dependent binding to cells. Contains 2 copies of a cytoplasmic immunoreceptor tyrosine-based inhibitor motif (ITIM). The phosphorylated ITIM motif can bind the SH2 domain of several SH2- containing phosphatases. In the immune response, may act as an inhibitory receptor upon ligand-induced tyrosine phosphorylation

MMMP Biomap #87 Page 4 by recruiting cytoplasmic phosphatase(s) via their SH2 domain(s) that block signal transduction through dephosphorylation of signaling molecules [1]

ONC : Is used as a therapeutic target for acute myeloid leukemia [2] CD34 - L- PHY: Adhesion molecule with a role in early [1] http://www.uniprot.org/uniprot/P28906 hematopoiesis by mediating the attachment of stem cells to the bone marrow or directly to stromal cells. Selectively expressed on hematopoietic progenitor cells and the small vessel endothelium of a variety of tissues [1]

ONC : - CD36 GP3B, PAS-4, Platelet collagen receptor, Collagen PHY : Expressed by platelets, macrophages [1] http://www.uniprot.org/uniprot/P16671. [2] Thrombospondin receptor, Fatty acid Thrombospondin and microvascular endothelial cells. McCarty MF, Med Hypotheses 2008, 70:419-23 translocase Scavenger receptor for oxidized LDL. Platelet adhesion. Directly mediates cytoadherence of Plasmodium falciparum parasitized erythrocytes. Defects in CD36 are the cause of platelet glycoprotein IV deficiency [1]

ONC : The ability of metronomic chemotherapy to induce endothelial apoptosis has been traced to increased endothelial expression of thrombospondin-1, which activates endothelial CD36 receptors, triggering the extrinsic apoptotic pathway [2] CD42a GP9, GPIX (glycoprotein IX, platelet) Von Willebrand factor PHY : The heteromeric complex of CD42 [1] http://www.uniprot.org/uniprot/P14770 proteins functions as the vWF receptor and mediates vWF-dependent platelet adhesion to blood vessels. The adhesion of platelets to injured vascular surfaces in the arterial circulation is a critical initiating event in hemostasis. Defects in GP9 are a cause of Bernard-Soulier syndrome (BSS) or giant platelet disease (GPD) [1]

ONC : -

MMMP Biomap #87 Page 5 CD42b GP1BA ( alpha Von Willebrand factor PHY : Acts as a heterodimer composed of GP- [1] http://www.uniprot.org/uniprot/P07359 polypeptide, platelet), CD42b alpha, Ib alpha and beta. See CD42a for more details glycocalicin [1]

ONC : - CD42c GP1BB (glycoprotein Ib beta Von Willebrand factor PHY : Acts as a heterodimer composed of GP- [1] http://www.uniprot.org/uniprot/P13224 polypeptide, platelet), CD42b beta Ib alpha and beta. See CD42a for more details [1]

ONC : - CD42d GP5 (glycoprotein V, platelet) Von Willebrand factor PHY : Acts as a heterodimer composed of GP- [1] http://www.uniprot.org/uniprot/P40197 Ib alpha and beta. See CD42a for more details [1]

ONC : - CD43 Sialophorin (SPN), leukosialin (LSN), PHY : This sialomucin is one of the major [1] http://www.uniprot.org/uniprot/P16150. [2] GPL115, Galactoglycoprotein (GALGP) of thymocytes and T Matsumoto M, J Immunol 2008, 181:3628-35 lymphocytes. Plays a role in the physicochemical properties of the T-cell surface and in lectin binding. This sialic acid rich protein presents carbohydrate ligands to selectins. Is a counter receptor for SN/SIGLEC-1. May inhibit ICAM-1 (CD54)- LFA-1 (CD11A/CD18) interaction. During T- cell activation is actively removed from the T- cell/antigen-presenting cell (APC) contact site thus suggesting a negative regulatory role in adaptive immune response [1]. Overall, can have both pro- and anti-adhesive properties [2]

ONC : - CD44 Indian blood group, MIC4, MDU2, MDU3, Hyaluronic acid PHY : Mediates cell-cell and cell-matrix [1] Heldin P, Connect Tissue Res 2008, 49:215- CD44R, HCELL (hematopoietic cell E- Selectin-E interactions through its affinity for a number of 8. [2] Naor D, Semin Cancer Biol 2008, 18:260- and L-selectin ligand), CSPG8 Selectin-L ligands such as hyaluronic acid (and other 7. [3] Ahrens T, J Invest Dermatol 2001, 116:93- ( 8), Selectin-P glycosamino glycans) [1], osteopontin, 101. [4] Bourguignon LY, Semin Cancer Biol 2008, 18:251-9. [5] Anderegg U, J Invest MC56, Pgp1 (phagocytic glycoprotein I) Collagen collagens, and matrix metalloproteinases Dermatol 2008, Epub ahead of print. [6] Laminin (MMP). Also involved in lymphocyte activation, http://www.uniprot.org/uniprot/P16070 Fibronectin recirculation and homing, and in hematopoiesis. Altered expression or dysfunction causes numerous pathogenic

MMMP Biomap #87 Page 6 phenotypes. Great protein heterogeneity due to numerous and post- translational modification events. Responsible for the Indian blood group system [6]

ONC : Interaction with hyaluronate plays an important role in cell migration, tumor growth and progression [2]. Expressed on many tumor types, supports cell migration and transmits survival signals, thereby being pro- oncogenic in many tumor models [2], including melanoma [3]. By activating RhoGTPase signaling, it leads to cytoskeleton reorganization and AKT activation, which in turn promote cell migration and survival, respectively [4]. Soluble CD44 (produced by ADAM10 sheddase activity) can abolish the cell proliferation-promoting effect of hyaluronate on melanoma cells [5] CD48 BLAST, BCM1, SLAMF2, B-lymphocyte CD2 PHY : Ligand for CD2, might facilitate [1] http://www.uniprot.org/uniprot/P09326 activation marker, OX-45, Lym-3 interaction between activated lymphocytes. Probably involved in regulating T-cell activation

ONC : - CD58 LFA-3 (lymphocyte function associated CD2 PHY : Ligand of the T-lymphocyte CD2 [1] http://www.uniprot.org/uniprot/P19256. [2] 3) glycoprotein: this interaction is important in Lee RV, Am J Clin Pathol 2005, 123:119-24 mediating thymocyte interactions with thymic epithelial cells and antigen-independent and - dependent interactions of T-lymphocytes with target cells and antigen-presenting cells (T cell activation) [1]

ONC : Potentially useful in the diagnosis and monitoring of precursor B-cell acute lymphoblastic leukemia (B-ALL), but only when blasts express high levels of CD58 [2] CD68 Macrosialin, GP110, SCARD1 Selectins PHY : Highly expressed by blood monocytes [1] http://www.uniprot.org/uniprot/P34810. [2] (scavenger receptor class D member 1) and tissue macrophages. Bind to tissue- and Mäkitie T, Invest Ophthalmol Vis Sci 2001, organ-specific lectins or selectins, allowing 42:1414-21. [3] Piras F, Cancer 2005, homing of macrophage subsets to particular 104:1246-54

MMMP Biomap #87 Page 7 sites [1]

ONC : Expressed in many tumor cell lines which could allow them to attach to selectins on vascular endothelium, facilitating their dissemination to secondary sites [1]. Tumor infiltrating macrophages (TIM) identified as CD68 positive cells are associated with the prognosis of uveal [2] but not skin [3] melanoma CD151 Tetraspanin 24, PETA-3, SFA-1 ITG alpha3-beta1 PHY: Essential for the proper assembly of the [1] http://www.uniprot.org/uniprot/P48509. [2] ITG alpha5-beta1 glomerular and tubular basement membranes Chien CW, Clin Cancer Res 2008, 14:8043-51. ITG alpha3-beta1 in kidney. Expressed in a variety of tissues [3] Yang XH, Cancer Res 2008, 68:3204-13. [4] ITG alpha6-beta4 including vascular endothelium and epidermis. Zijlstra A, Cancer Cell 2008, 13:221-34 CD9 Defines the MER2=RAPH1 antigen of the CD181 RAPH blood group system. Defects in CD151 are the cause of nephropathy with pretibial epidermolysis bullosa and deafness (NPEBD) [1]

ONC : Regulation of CD151 by hypoxia controls cell adhesion and metastasis in colorectal cancer [2]. CD151 accelerates breast cancer by regulating alpha 6 function, signaling, and molecular organization [3]. However, loss of cancer cell migration in vivo is the result of enhanced tumor cell-matrix interactions promoted by CD151, which prevent dissociation by individual cells and leads to a subsequent inhibition of invasion and intravasation at the site of the primary tumor [4] CD164 Sialomucin, MUC24, endolyn ? PHY : Involved in cell adhesion and migration. [1] Forde S, Blood 2007, 109:1825-33. [2] Forms complexes with the motility-stimulating Havens AM, BMC Cancer 2006, 6:195. [3] chemokine receptor CXCR4 in response to http://www.uniprot.org/uniprot/Q04900 the CXCR4 ligand, CXCL12/SDF1 [1]

ONC : May participate in the homing of prostate cancer cells to the bone marrow [2]. Expressed in small intestine, colon, lung, thyroid and in colorectal and pancreatic adenocarcinoma [3]

MMMP Biomap #87 Page 8 CD209 CD-SIGN1 (Dendritic cell-specific ICAM- ICAM1 PHY : Mainly expressed on dendritic cells [1] http://www.uniprot.org/uniprot/Q9NNX6 3-grabbing non-integrin 1), C-type lectin ICAM2 (DC). May act as a DC rolling receptor that domain family 4 member L ICAM3 mediates transendothelial migration of DC from blood to tissues. Seems to regulate DC- induced T cell proliferation by binding to ICAM3 on T cells in the immunological synapse formed between DC and T cells. Pathogen-recognition receptor expressed on the surface of immature DC and involved in initiation of primary immune response [1]

ONC : - CD226 DNAM1 (DNAX accessory molecule 1) CD112 PHY : Receptor involved in intercellular [1] http://www.uniprot.org/uniprot/Q15762 CD155 adhesion, lymphocyte signaling, cytotoxicity and lymphokine secretion mediated by cytotoxic T-lymphocyte (CTL) and NK cell [1]

ONC : - CD229 LY9, T-lymphocyte surface antigen Ly-9 CD229 (?) PHY : May participate in adhesion reactions [1] http://www.uniprot.org/uniprot/Q9HBG7 between T lymphocytes and accessory cells by homophilic interaction [1]

ONC : - CD248 Endosialin, TEM1 (tumor endothelial MAC-2 PHY : Interaction of endosialin/TEM1 with [1] Tomkowicz B, Proc Natl Acad Sci USA 2007, marker 1) extracellular matrix proteins mediates cell 104:17965-70. [2] Rouleau C, Clin Cancer Res adhesion and migration [1] 2008, 14:7223-36. [3] Becker R, FASEB J 2008, 22:3059-67 ONC : Is expressed in stromal cells, endothelial cells, and pericytes within various tumors, as well as by some malignant cells [2]. Is a binding partner of metastasis-related protein Mac-2 BP/90K (extracellular ligand) [3]

MMMP Biomap #87 Page 9 CDH1 E- (epithelial), Cadherin 1, CDH1 PHY : Acts as a homodimer. Involved in cell- [1] Jeanes A, Oncogene 2008, 27:6920-9. [2] uvomorulin, CD324 ITG alphaE-beta7 cell adhesion, mobility and proliferation of Cavallaro U, Nat Rev Cancer 2004, 4:118-32. epithelial cells. The cytoplasmic domain [3] Stemmler MP, Mol Biosyst 2008, 4:835-50. interacts with beta-catenin to form the [4] Mariotti A, Expert Opin Investig Drugs 2007, 16:451-65. [5] Rodriguez M, Cancer Res 2008, cadherin/catenin adhesion complex (adherens 68:7872-81. [6] Smit DJ, Int J Cancer 2007, junction, see below Figure), which connects to 121:2653-60. [7] Kippenberger S, Melanoma the actin skeleton through alpha-catenin Res 2006, 16:393-403. [8] Robert G, Cancer Res 2006, 66:7516-23. [9] Kreizenbeck GM, ONC : Is believed to act as a tumor suppressor Cancer Epidemiol Biomarkers Prev 2008, gene (TSG) in different types of carcinoma, 17:949-58 mainly by favoring cell adhesion/polarity, preventing beta-catenin from translocation to the nucleus and inhibiting mitogenic signaling through its interaction with growth factor receptors [1-3]. Loss of E-cadherin and acquisition of N-cadherin expression (the "cadherin switch") is a hallmark of epithelial- mesenchymal transition (EMT), a key event in cancer progression/ invasiveness [4]. CDH1 loss promotes melanoma progression in preclinical models [5-8] and is associated with worse prognosis of patients with melanoma [9] (CDHs)

The cadherin superfamily of cell-cell adhesion proteins includes classical cadherins (CDH), (PCDH) and atypical cadherins (FAT, Dachsous, and Flamingo cadherins). CDHs are single-pass transmembrane, calcium-dependent cell adhesion proteins. They preferentially interact with themselves in a homophilic manner in connecting cells; cadherins may thus contribute to the sorting of heterogeneous cell types. Besides their adhesive properties, cadherins may act by transferring intracellular signals through interaction with a complex network of cytoskeletal and signaling molecules. They may signal in different ways: through direct activation of signaling pathways, through interaction with cell-specific growth factor receptors or by controlling the translocation to the nucleus of beta-catenin and other transcription factors. Cadherins play pivotal roles in important morphogenetic and differentiation processes during development, and in maintaining tissue integrity and homeostasis. Changes in cadherin expression throughout development enable differentiation and the formation of various organs. In addition to these functions, cadherins have strong implications in carcinogenesis, as exemplified by the fact that frequently tumor cells show deregulated cadherin expression and inappropriate switching among family members. REFERENCES: [1] Pokutta S, Annu Rev Cell Dev Biol 2007, 23:237-61. [2] Stemmler MP, Mol Biosyst 2008, 4:835-50. [3] Suzuki SC, Dev Growth Differ 2008, 50 Suppl 1:S119-30

MMMP Biomap #87 Page 10 CDH2 N-cadherin (neuronal), Cadherin 2, CDH2 PHY : Plays a key role in cell migration. In [1] Derycke LD, Int J Dev Biol 2004, 48:463-76. CDHN, CD325 embryogenesis, N-cadherin is the key [2] Hansen SM, Cell Mol Life Sci 2008, 65:3809- molecule during gastrulation and neural crest 21. [3] Cavallaro U, Curr Opin Investig Drugs development. N-cadherin mediated contacts 2004, 5:1274-8. [4] Mariotti A, Expert Opin Investig Drugs 2007, 16:451-65. [5] Augustine activate several pathways like Rho GTPases CK, Cancer Res 2008, 68:3777-84. [6] Watson- and function in tyrosine kinase signaling, with Hurst K, Cancer Biol Ther 2006, 5:1375-82. [7] special regard to the fibroblast growth factor Liu ZJ, Cancer Res 2006, 66:4182-90. [8] receptor (FGFR) pathway [1,2] Kuphal S, Oncogene 2006, 25:248-59

ONC : Is believed to act as an oncogene in different tumor types, mainly by favoring malignant cell motility, migration and invasiveness [3]. Loss of E-cadherin and acquisition of N-cadherin expression (the "cadherin switch") is a hallmark of epithelial- mesenchymal transition (EMT), a key event in cancer progression/ invasiveness [4]. Several lines of evidence suggest that CDH2 plays a significant role also in melanoma progression/ aggressiveness in preclinical models [5-8]

CDH3 P-cadherin (placental), Cadherin 3, CDH3 PHY : Defects in CDH3 are the cause of [1] http://www.uniprot.org/uniprot/P22223. [2] CDHP, PCAD hypotrichosis with juvenile macular dystrophy Imai K, Clin Cancer Res 2008, 14:6487-95. [3] (HJMD) and ectodermal dysplasia with Bryan RT, J Pathol 2008, 215:184-94. [4] ectrodactyly and macular dystrophy (EEM) [1] Gravdal K, Clin Cancer Res 2007, 13:7003-11. [5] Paredes J, Breast Cancer Res 2007, 9:214. [6] Kreizenbeck GM, Cancer Epidemiol ONC : Considered a novel tumor-associated Biomarkers Prev 2008, 17:949-58. [7] Bauer R, antigen (TAA) and thus a possible target for J Clin Pathol 2006, 59:699-705. [8] Bachmann immunotherapy for different carcinomas [2]. IM, Clin Cancer Res 2005, 11(24 Pt 1):8606-14 Usually associated with worse prognosis in patients with carcinomas [3,4], while in patients with melanoma the findings are conflicting [6-8] CDH4 R-cadherin (retinal), Cadherin 4 CDH4 PHY : Expressed mainly in brain but also found [1] http://www.uniprot.org/uniprot/P55283. [2] in other tissues [1] Kucharczak J, Cancer Res 2008, 68:6559-68. [3] Miotto E, Cancer Res 2004, 64:8156-9 ONC : Inhibits myogenesis and induces myoblast transformation via Rac1 GTPase [2]. MMMP Biomap #87 Page 11 On the other hand, frequent aberrant methylation of the CDH4 gene promoter in human colorectal and gastric cancer makes it a candidate tumor suppressor gene [3] CDH5 VE-cadherin (vascular endothelial), CDH5 PHY : Plays an important role in endothelial [1] Taveau JC, Biochem Soc Trans 2008, 36(Pt Cadherin 5, CD144 cell biology (with special regard to 2):189-93. [2] Dejana E, J Cell Sci 2008, 121(Pt angiogenesis) through control of the 13):2115-22. [3] Lopez D, Arch Biochem organization of intercellular junctions. Biophys 2008, Epub ahead of print. [4] Menon C, Ann Surg 2006, 244:781-91. [5] Hess AR, Associates with alpha-catenin forming a link to Cancer Biol Ther 2006, 5:228-33. [6] Prandini the cytoskeleton. Mainly expressed in MH, Oncogene 2005, 24:2992-3001 endothelial tissues and brain. In vascular endothelium, adherens junctions between endothelial cells are composed of VE- cadherin, which is crucial for the proper assembly of vascular structures and control of vascular permeability and leukocyte diapedesis [1,2]

ONC : Tumor-induced upregulation of TWIST, SNAIL and SLUG represses the activity of the human VE-cadherin promoter [3]. -alpha (TNF) damages tumor blood vessel integrity by targeting VE-cadherin [4]. VE-cadherin regulates EphA2 in aggressive melanoma cells with implications for vasculogenic mimicry [5]. Neovessels in tumor grafts and Matrigel implants harbor strong staining, indicating that promoter activity is enhanced in angiogenic situations [6] CDH6 K-cadherin (kidney), Cadherin 6 CDH6 PHY : Highly expressed in brain, cerebellum, [1] http://www.uniprot.org/uniprot/P55285. [2] and kidney. Lung, pancreas, and gastric Xiang YY, Cancer Res 1994, 54:3034-41 mucosa show a weak expression [1]

ONC : Expressed in kidney carcinoma [2] CDH7 Cadherin 7, CDH7L1 CDH7 PHY : - [1] Moore R, Oncogene 2004, 23:6726-35. [2] Winklmeier A, Cancer Sci 2009, 100:261-8 ONC : Might play a role in melanocyte transformation: the majority of the tested malignant melanoma cell lines produce N- cadherin and/or cadherin-7 whereas melanocyte cell lines do not (the converse MMMP Biomap #87 Page 12 was observed for E-cadherin) [1]. In contrast, CDH7 - which binds to melanoma migration promoting molecule MIA - is upregulated in metastatic as compared to primary melanomas and its forced overexpression inhibits metastatic melanoma cell migration [2]

CDH8 Cadherin 8 CDH8 PHY : Mainly expressed in brain. Found in [1] http://www.uniprot.org/uniprot/P55286. [2] Lu certain nerve cell lines, such as retinoblasts, Y, PLoS Med 2006, 3(12):e467 glioma cells and neuroblasts [1]

ONC : Belongs to a signature that predicts survival of patients with non- small cell lung cancer (NSCLC) [2] CDH9 Cadherin 9, T1-cadherin CDH9 PHY : ? -

ONC : - CDH10 Cadherin 10, T2-cadherin CDH10 PHY : Predominantly expressed in brain. Also [1] http://www.uniprot.org/uniprot/Q9Y6N8. [2] found in adult and fetal kidney [1] Walker MM, Mod Pathol 2008, 21:85-95

ONC : Is a marker for human prostate luminal epithelial cells while is not expressed in prostate cancer [2] CDH11 OB-cadherin (osteoblast), Cadherin 11 CDH11 PHY : Expressed mainly in brain but also found [1] Nakajima G, Cancer Proteomics in other tissues/cells (e.g. osteoblasts) 2008, 5:37-42

ONC : Its expression is associated with survival in patients with osteosarcoma [1] CDH12 Cadherin 12, N-cadherin 2 (brain) CDH12 PHY : Mainly expressed in brain [1] [1] http://www.uniprot.org/uniprot/P55289

ONC : - CDH13 H-cadherin (heart), Cadherin 13 CDH13 PHY : Highly expressed in heart. In the CNS, [1] http://www.uniprot.org/uniprot/P55290. [2] Jin expressed in cerebral cortex, medulla, Z, Int J Cancer 2008, 123:2331-6. [3] Suehiro Y, hippocampus, amygdala, thalamus and Clin Cancer Res 2008, 14:3354-61. [4] Feng Q, substantia nigra. May act as a negative Cancer Epidemiol Biomarkers Prev 2008, 17:645-54. [5] Thomas G, Nat Genet 2008, regulator of neural cell growth [1] 40:310-5

ONC : Promoter hypermethylation of CDH13 is found in esophageal adenocarcinoma [2], endometrial carcinoma [3], non small cell lung

MMMP Biomap #87 Page 13 carcinoma [4]. Also associated (recessive model) with prostate cancer risk [5] CDH15 M-cadherin (myotubule), Cadherin 15, CDH15 PHY : M-cadherin is part of the myogenic [1] http://www.uniprot.org/uniprot/P55291. [2] CDH14 program and may provide a trigger for terminal Yamada S, Anticancer Res 2007, 27(4B):2269- muscle differentiation [1] 74

ONC : Its promoter is found methylated in hepatocellular carcinoma (HCC), which correlates with poor prognosis [2] CDH16 KSP-cadherin (kidney specific), Cadherin CDH16 PHY : Mainly expressed in kidney [1] Thedieck C, Br J Cancer. 2005 Jun 16 6;92(11):2010-7 ONC : Downregulated in renal cell carcinoma [1] CDH17 LI-cadherin (liver, intestine), Cadherin 17 CDH17 PHY : May have a role in the morphological [1] Kwak JM, Dis Colon Rectum 2007, 50:1873- organization of liver and intestine 80. [2] Dong W, Dig Dis Sci 2007, 52:536-42. [3] Park SS, Ann Surg Oncol 2007, 14:94-9. [4] Ito R, Virchows Arch 2005, 447:717-22 ONC : Conflicting results on its association with prognosis of gastrointestinal carcinomas [1-3] CDH18 Cadherin 18, EY-cadherin, CDH14 CDH18 PHY : ? -

ONC : - CDH19 Cadherin 19, CDH7L2 CDH19 PHY : Expressed in many tissues, with the [1] http://www.uniprot.org/uniprot/Q9H159 exception of uterus [1]

ONC : - CDH20 Cadherin 20, CDH7L3 CDH20 PHY : Expressed in placenta, adult brain, and [1] http://www.uniprot.org/uniprot/Q9HBT6. [2] fetal brain [1] Moore R, Oncogene 2004, 23:6726-35

ONC : Might play a role in melanocyte transformation: the majority of the tested malignant melanoma cell lines produced N- cadherin and/or cadherin-20 whereas melanocyte cell lines did not (the converse was observed for E-cadherin) [2] CDH22 PB-cadherin (pituitary, brain), Cadherin CDH22 PHY : May have a role in the morphological [1] http://www.uniprot.org/uniprot/Q9UJ99 22 organization of pituitary gland and brain tissues [1]

MMMP Biomap #87 Page 14 ONC : - CDH23 Cadherin 23, Otocadherin CDH23 PHY : Organization of the stereocilia bundle of [1] http://www.uniprot.org/uniprot/Q9H251 hair cells in the cochlea and the vestibule during embryonic development. Particularly strong expression in the retina. Defects in CDH23 are the cause of (association of retinitis pigmentosa and sensorineural deafness) [1]

ONC : - CDH24 Cadherin 24, CDH11L CDH24 PHY : ? -

ONC : - CDH26 Cadherin 26, VR20 CDH26 PHY : ? -

ONC : - CDH29 Cadherin 29 ? PHY : ? -

ONC : - CEACAM1 -related cell ? PHY : ? [1] Luo W, Oncogene 1997, 14:1697-704. [2] adhesion molecule 1, BGP (biliary Gaur S, Mol Cancer 2008, 7:46. [3] Markel G, Immunology 2008, Epub ahead of print. [4] glycoprotein), CD66a ONC : Conflicting findings on non-melanoma Ebrahimnejad A, Am J Pathol 2004, 165:1781-7 tumors [1,2]. Protects melanoma from immune attack [3] and increases melanoma invasiveness [4] CEACAM3 Carcinoembryonic antigen-related cell ? PHY : Major granulocyte receptor for [1] Salama I, Eur J Surg Oncol 2008, 34:357-64 adhesion molecule 3, CGM1 (CEA gene microorganism recognition and family member 1), CD66d ONC : Cytosolic domain interacts with S100A9, a putative tumor suppressor protein [1] CEACAM4 Carcinoembryonic antigen-related cell ? PHY : Mainly expressed by granulocytes - adhesion molecule 4, CGM7 (CEA gene family member 7) ONC : - CEACAM5 Carcinoembryonic antigen-related cell Selectin-E [1] PHY : Found in fetal colon and in GI [1] Thomas SN, J Biol Chem 2008, 283:15647- adhesion molecule 5, CEA, CD66e Selectin-L [1] (gastrointestinal) adenocarcinomas 55. [2] Ravindranath MH, Anticancer Res 2000, 20:3083-92 ONC : Routinely used as serum marker for GI carcinomas. Is not expressed by human melanoma cell lines [2] MMMP Biomap #87 Page 15 CEACAM6 Carcinoembryonic antigen-related cell ? PHY : ? [1] Han SU, Oncogene 2008, 27:675-83. [2] adhesion molecule 6, NCA, CD66c Ordonez C, J Cell Physiol 2007, 210:757-65 ONC : Overexpressed in a variety of epithelial , promotes tumor invasiveness [1]. Is a TGF-beta/SMAD3 target [2] CEACAM7 Carcinoembryonic antigen-related cell ? PHY : Expressed by normal colon epithelial [1] Thompson J, Cancer Res 1997, 57:1776-84. adhesion molecule 7, CGM2 (CEA gene cells [2] Kinugasa T, Int J Cancer 1998, 76:148-53 family member 2) ONC : Downregulated in colon [1] and upregulated in gastric carcinoma cells [2] CEACAM8 Carcinoembryonic antigen-related cell ? PHY : Expressed by leukocytes of normal bone [1] Berling B, Cancer Res 1990, 50:6534-9. [2] adhesion molecule 8, CGM6 (CEA gene marrow Lasa A, Ann Hematol 2008, 87:205-11 family member 6), CD66b ONC : Expressed by leukemia cells [1,2] CEACAM16 Carcinoembryonic antigen-related cell ? PHY : ? [1] Zebhauser R, Genomics 2005, 86:566-80 adhesion molecule 16 ONC : - CEACAM18 Carcinoembryonic antigen-related cell ? PHY : ? [1] Zebhauser R, Genomics 2005, 86:566-80 adhesion molecule 18 ONC : - CEACAM19 Carcinoembryonic antigen-related cell ? PHY : ? - adhesion molecule 19, CEAL1 ONC : - CEACAM20 Carcinoembryonic antigen-related cell ? PHY : ? [1] Zebhauser R, Genomics 2005, 86:566-80 adhesion molecule 20 ONC : - CEACAM21 Carcinoembryonic antigen-related cell ? PHY : ? - adhesion molecule 21 ONC : - CHL1 Cell adhesion molecule homologous to L1CAM PHY : Involved in nervous system [1] Qin YR, Int J Cancer 2008, 123:826-30. [2] L1CAM, CALL, L1CAM2 ITG alpha1-beta1 development. Cleaved by metalloprotease Tschentscher F, Cancer Res 2003, 63:2578-84 ITG alpha2-beta1 ADAM8. Recruits ANK3 to plasma membrane

ONC : Candidate tumor suppressor gene for esophageal carcinoma [1] and uveal melanoma [2] Claudin 1 CLDN1, SEMP1 (senescence-associated Claudins PHY : Calcium-independent cell-adhesion [1] http://www.uniprot.org/uniprot/O95832. [2] epithelial 1), ILVASC TJP1 activity through the formation of tight junctions. Harten SK, Mol Biol Cell 2008, Epub ahead of print. [3] Chao YC, Am J Respir Crit Care Med MMMP Biomap #87 Page 16 TJP2 Strongly expressed in liver and kidney. 2008, Epub ahead of print. [4] Dos Reis PP, TJP3 Expressed in heart, brain, spleen, lung and Cancer 2008, 113:3169-80. [5] Fritzsche FR, testis. Co-receptor for HCV entry. Defects in Clin Cancer Res 2008, 14:7035-42. [6] Leotlela CLDN1 are the cause of neonatal ichthyosis- PD, Oncogene 2007, 26:3846-56. [7] Cohn ML, J Cutan Pathol 2005, 32:533-6 sclerosing cholangitis syndrome (NISCH) also called ichthyosis with leukocyte vacuoles alopecia and sclerosing cholangitis (ILVASC) [1]

ONC : Conflicting data. In renal cell carcinoma (RCC), VHL loss leads to epithelial mesenchymal transition (EMT) by downregulation not only of E-cadherin expression (adherens junction) but also and claudin-1 (tight junction) [2]. Plus, claudin-1 is a metastasis suppressor and correlates with favorable clinical outcome of patients with lung adenocarcinoma [3]. However, claudin-1 overexpression increases invasion and is associated with aggressive histological features in oral squamous cell carcinoma [4], and is an independent negative prognosticator for patients with clear cell renal cell carcinoma [5]. In melanoma, claudin-1 overexpression is enhanced by PKC and contributes to cell motility [6], but loss of claudin-1 expression in melanoma-associated vessels correlates with acquisition of metastatic phenotype [7] Claudin 2 CLDN2 Claudins PHY : Calcium-independent cell-adhesion [1] Kim TH, Histopathology 2008, 53:48-55. [2] TJP1 activity through the formation of tight junctions Weber CR, Lab Invest 2008, 88:1110-20. [3] TJP2 Mima S, Carcinogenesis 2008, 29:1994-2000 TJP3 ONC : Conflicting data. Downregulation of claudin-2 in breast carcinomas is associated with advanced disease [1]. However, claudin-2 expression is elevated in inflammatory bowel disease and may contribute to early neoplastic transformation [2]; plus, inhibition of claudin-2 expression by NSAID contributes to NSAID- dependent inhibition of invasion of cancer cells in vitro [3]

MMMP Biomap #87 Page 17 Claudin 3 CLDN3, CPER2 (Clostridium perfringens TJP1 PHY : Calcium-independent cell-adhesion [1] Rangel LB, Clin Cancer Res 2003, 9:2567- enterotoxin receptor 2) TJP2 activity through the formation of tight junctions. 75. [2] Konecny GE, Gynecol Oncol 2008, TJP3 Clostridium perfringens enterotoxin (CPE) 109:263-9. [3] Kominsky SL, Am J Pathol 2004, induces cytolysis very rapidly through binding 164:1627-33. [4] Agarwal R, Cancer Res 2005, 65:7378-85 to its receptors CLDN3 and CLDN4

ONC : Overexpressed in ovarian [1], endometrial [2] and breast [3] carcinomas. Enhances invasion and is associated with increased matrix metalloproteinase-2 (MMP-2) activity [4]

Claudin 4 CLDN4, CPER1 (Clostridium perfringens Claudins PHY : Calcium-independent cell-adhesion [1] Landers KA, Br J Cancer 2008, 99:491-501. enterotoxin receptor 1) TJP1 activity through the formation of tight junctions. [2] Litkouhi B, Neoplasia 2007, 9:304-14. [3] TJP2 Clostridium perfringens enterotoxin (CPE) Santin AD, Cancer 2007, 109:1312-22. [4] TJP3 induces cytolysis very rapidly through binding Agarwal R, Cancer Res 2005, 65:7378-85. [5] Ueda J, Pathobiology 2007, 74:32-41 to its receptors CLDN3 and CLDN4

ONC : Overexpressed in different carcinoma types (e.g. prostatic [1], ovarian [2], endometrial [3]). Plus, claudin-4 expression in ovarian epithelial cells enhances invasion and is associated with increased matrix metalloproteinase-2 activity. However, decreased claudin-4 expression at the invasive front correlates colorectal cancer

MMMP Biomap #87 Page 18 invasion and metastasis [5] Claudin 5 CLDN5, AWAL, TMVCF ( transmembrane TJP1 PHY : Calcium-independent cell-adhesion [1] Soini Y, Histopathology 2005, 46:551-60 protein deleted in velo-cardio-facial TJP2 activity through the formation of tight junctions syndrome) TJP3 ONC : Claudins 1, 2, 3, 4, 5 and 7 are expressed in different carcinomas (though with tumor type-specific differences). In contrast to epithelial tumors, lymphomas do not express claudins and most soft tissue tumors and nevocytic lesions are negative or show weaker, mainly cytoplasmic positivity for some claudins [1] Claudin 6 CLDN6 TJP1 PHY : Calcium-independent cell-adhesion [1] Osanai M, Cancer Sci 2007, 98:1557-62 TJP2 activity through the formation of tight junctions TJP3 ONC : Epigenetic silencing of claudin-6 promotes anchorage-independent growth of breast carcinoma cells [1] Claudin 7 CLDN7, CEPTRL2 TJP1 PHY : Calcium-independent cell-adhesion [1] Nakayama F, Pathobiology 2008, 75:177-85. TJP2 activity through the formation of tight junctions [2] Darido C, Cancer Res 2008, 68:4258-68. [3] TJP3 Kuhn S, Mol Cancer Res 2007, 5:553-67. [4] Oshima T, Oncol Rep 2008, 19:953-9. [5] Lioni ONC : Conflicting data. Downregulated in M, Am J Pathol 2007, 170:709-21. [6] Kominsky breast cancer, where its loss correlates with SL, Oncogene 2003, 22:2021-33 high grade tumors [6]. Hypermethylation- modulated downregulation of claudin-7 expression promotes the progression of colorectal carcinoma [1]. TCF-4 maintains low levels of claudin-7 at the bottom of colonic crypts, acting via SOX-9: this negative regulation is defective in colorectal cancer, possibly due to decreased SOX-9 activity, and the resulting claudin-7 overexpression promotes a loss of tumor cell polarization and contributes to tumorigenesis [2]. Plus, complex of EpCAM, claudin-7, CD44 variant isoforms, and tetraspanins promotes colorectal cancer progression [3]. However, reduced expression of the claudin-7 gene might lead to venous invasion and liver metastasis in colorectal cancer [4]. Plus, downregulation of claudin-7 leads to loss of E- cadherin expression and the increased MMMP Biomap #87 Page 19 invasion of esophageal squamous cell carcinoma cells [5] Claudin 8 CLDN8 TJP1 PHY : Calcium-independent cell-adhesion [1] Gröne J, Int J Colorectal Dis 2007, 22:651-9 TJP2 activity through the formation of tight junctions TJP3 ONC : Downregulated in colorectal cancer at mRNA level but not protein level [1] Claudin 9 CLDN9 ? PHY : Calcium-independent cell-adhesion [1] http://www.uniprot.org/uniprot/O95484 activity through the formation of tight junctions [1]

ONC : - Claudin 10 CLDN10, OSP-L, CPETRL3 ? PHY : Calcium-independent cell-adhesion [1] http://www.uniprot.org/uniprot/P78369. [2] Ip activity through the formation of tight junctions YC, Mol Cancer Ther 2007, 6:2858-67. [3] [1] Cheung ST, Clin Cancer Res 2005, 11(2 Pt 1):551-6 ONC : Hepatocellular carcinoma (HCC) invasion is inhibited by suppression of claudin- 10 [2] and claudin-10 expression is associated with recurrence of primary HCC [3] Claudin 11 CLDN11, OTM (oligodendrocyte Tetraspanin-3 PHY : Calcium-independent cell-adhesion [1] http://www.uniprot.org/uniprot/O75508 transmembrane protein) activity through the formation of tight junctions [1]

ONC : - Claudin 12 CLDN12 ? PHY : Calcium-independent cell-adhesion [1] Gröne J, Int J Colorectal Dis 2007, 22:651-9 activity through the formation of tight junctions [1]

ONC : Upregulated in colorectal cancer at mRNA level but not protein level [1]. Claudin 14 CLDN14 ? PHY : Calcium-independent cell-adhesion [1] http://www.uniprot.org/uniprot/O95500 activity through the formation of tight junctions. Defects in CLDN14 are the cause of non- syndromic sensorineural deafness autosomal recessive type 29 (DFNB29) [1]

ONC : - Claudin 15 CLDN15 ? PHY : Calcium-independent cell-adhesion [1] http://www.uniprot.org/uniprot/P56746 activity through the formation of tight junctions MMMP Biomap #87 Page 20 [1]

ONC : - Claudin 16 CLDN16, paracellin-1 ? PHY : Plays a major role in tight junction- [1] http://www.uniprot.org/uniprot/Q9Y5I7. [2] specific obliteration of the intercellular space, Martin TA, J Cell Biochem 2008, 105:41-52. [3] through calcium-independent cell-adhesion Fluge Ø, Thyroid 2006, 16:161-75 activity. Kidney-specific expression. Involved in paracellular magnesium reabsorption. Defects in CLDN16 are the cause of hypomagnesemia type 3 (HOMG3) [1]

ONC : Claudin-16 reduces the aggressive behavior of human breast cancer cells [2]. Claudin-16 and claudin-1 are upregulated in classic papillary thyroid carcinoma (PTC) but not in aggressive/poorly differentiated PTC [3] Claudin 17 CLDN17 ? PHY : Plays a major role in tight junction- [1] http://www.uniprot.org/uniprot/P56750 specific obliteration of the intercellular space, through calcium-independent cell-adhesion activity [1]

ONC : - Claudin 18 CLDN18, SFTPJ (surfactant associated ? PHY : Plays a major role in tight junction- [1] Sentani K, Am J Surg Pathol 2008, 32:1182- protein J) specific obliteration of the intercellular space, 9. [2] Karanjawala ZE, Am J Surg Pathol 2008, through calcium-independent cell-adhesion 32:188-96. [3] Sahin U, Clin Cancer Res 2008, activity 14:7624-34

ONC : Immunohistochemical staining for claudin-18 is useful in the diagnosis of gastrointestinal signet ring cell carcinoma [1]. Overexpressed in pancreatic cancer [2]. Claudin-18 splice variant 2 is a pan-cancer target suitable for therapeutic development [3] Claudin 19 CLDN19 ? PHY : Plays a major role in tight junction- [1] http://www.uniprot.org/uniprot/Q8N6F1 specific obliteration of the intercellular space, through calcium-independent cell-adhesion activity. Defects in CLDN19 are the cause of hypomagnesemia renal with ocular involvement (HOMGO) [1]

MMMP Biomap #87 Page 21 ONC : - Claudin 20 CLDN20 ? PHY : Plays a major role in tight junction- [1] http://www.uniprot.org/uniprot/P56880 specific obliteration of the intercellular space, through calcium-independent cell-adhesion activity [1]

ONC : - Claudin 22 CLDN22 ? PHY : Plays a major role in tight junction- [1] http://www.uniprot.org/uniprot/Q8N7P3 specific obliteration of the intercellular space, through calcium-independent cell-adhesion activity [1]

ONC : - Claudin 23 CLDN23 ? PHY : Plays a major role in tight junction- [1] http://www.uniprot.org/uniprot/Q96B33. [2] specific obliteration of the intercellular space, Katoh M, Int J Mol Med 2003, 11:683-9 through calcium-independent cell-adhesion activity. Expressed in germinal center B-cells, placenta, stomach [1]

ONC : Frequently downregulated in intestinal- type gastric cancer [2] DCHS1 Dachsous protein homolog 1, PCDH16, ? PHY : Calcium-dependent cell-adhesion [1] http://www.uniprot.org/uniprot/Q96JQ0 CDH19, fibroblast cadherin 1 protein belonging to the cadherin superfamily. Expressed in fibroblasts [1]

ONC : - DCHS2 Dachsous protein homolog 2, PCDH23, ? PHY : Calcium-dependent cell-adhesion [1] http://www.uniprot.org/uniprot/Q6V1P9 CDH27 protein belonging to the cadherin superfamily. Expressed in cerebral cortex and testis [1]

ONC : - DSC1 1, CDHF1 PHY : Component of intercellular [1] http://www.uniprot.org/uniprot/Q08554. [2] junctions, which connect adjacent cells and Khan K, Br J Cancer 2006, 95:1367-70 are linked to the cytoskeleton's intermediate filaments (e.g. cytokeratins, desmin, vimentin, nestin). Strongly expressed in epidermis, less in lymph node and tongue. Calcium may be bound by the cadherin-like repeats. May contribute to epidermal cell stratification [1]

MMMP Biomap #87 Page 22 ONC : (desmosomal cadherin family of cell-cell adhesion molecules) exhibit tissue-specific patterns of expression (e.g. only DSC2 is expressed in normal colonic epithelium). In colorectal carcinoma cells desmocollin switching leads to downregulation of DSC2 and de novo expression of DSC1 and DSC3 [2] DSC2 Desmocollin 2, CDHF2 Desmoglein PHY : Component of intercellular desmosome [1] http://www.uniprot.org/uniprot/Q02487. [2] junctions, which connect adjacent cells and Khan K, Br J Cancer 2006, 95:1367-70 are linked to the cytoskeleton's intermediate filaments (e.g. cytokeratins, desmin, vimentin, nestin). Expressed in epithelia, myocardium and lymph nodes. Calcium may be bound by the cadherin-like repeats. May contribute to epidermal cell positioning (stratification) by mediating differential adhesiveness between cells that express different isoforms. Defects in DSC2 are the cause of familial arrhythmogenic right ventricular dysplasia 11 (ARVD11) [1]

ONC : The desmocollins (desmosomal cadherin family of cell-cell adhesion molecules) exhibit tissue-specific patterns of expression (e.g. only DSC2 is expressed in normal colonic epithelium). In colorectal cancer desmocollin switching leads to downregulation of DSC2 and de novo expression of DSC1 and DSC3 [2] DSC3 Desmocollin 3, CDHF3 Desmoglein PHY : Component of intercellular desmosome [1] http://www.uniprot.org/uniprot/Q14574. [2] junctions, which connect adjacent cells and Khan K, Br J Cancer 2006, 95:1367-70

MMMP Biomap #87 Page 23 are linked to the cytoskeleton's intermediate filaments (e.g. cytokeratins, desmin, vimentin, nestin). Expressed in epidermis, buccal mucosa, and cervix. Calcium may be bound by the cadherin-like repeats. May contribute to epidermal cell positioning (stratification) by mediating differential adhesiveness between cells that express different isoforms [1]

ONC : The desmocollins (desmosomal cadherin family of cell-cell adhesion molecules) exhibit tissue-specific patterns of expression (e.g. only DSC2 is expressed in normal colonic epithelium). In colorectal cancer desmocollin switching leads to downregulation of DSC2 and de novo expression of DSC1 and DSC3 [2]

DSCAM Down syndrome cell adhesion molecule, DSCAM PHY : Mediates cation-independent homophilic [1] Schmucker D, Nat Rev Neurosci 2007, CHD2-42, CHD2-52 binding activity. Could be involved in nervous 8:915-20 system development

ONC : - DSCAML1 DSCAM like 1 DSCAML1 PHY : Mediates cation-independent homophilic [1] Kowarz E, Leukemia 2007, 21:1232-8 binding activity. Could be involved in nervous system development

ONC : In acute leukemia cells, one of the several different translocation partner of mixed lineage leukemia (MLL) gene [1] DSG1 Desmoglein 1, CDHF4 Desmocollin PHY : Component of intercellular desmosome [1] http://www.uniprot.org/uniprot/Q02413. [2] junctions, which connect adjacent cells and Romani VC, BMC Cancer 2008, 8:373. [3] are linked to the cytoskeleton's intermediate Wong MP, Pathology 2008, 40:611-6. [4] filaments (e.g. cytokeratins, desmin, vimentin, Fukuoka J, Hum Pathol 2007, 38:276-83. [5] Schmitt CJ, J Invest Dermatol 2007, 127:2191- nestin). Expressed in epidermis, tongue, tonsil 206. [6] Li G, Oncogene 2001, 20:8125-35 and esophagus. Calcium may be bound by the cadherin-like repeats. Defects in DSG1 are the cause of palmoplantar keratoderma striate

MMMP Biomap #87 Page 24 type 1 (SPPK1) [1]

ONC : Loss in (desmosomal proteins of the cadherin family) is described in different tumor types, and is believed to promote cancer invasiveness [2-4]. In melanoma, desmogleins can be expressed but do not form [5] and are downregulated by c-MET during progression [6] DSG2 Desmoglein 2, CDHF5 Desmocollin PHY : Component of intercellular desmosome [1] http://www.uniprot.org/uniprot/Q14126. [2] junctions, which connect adjacent cells and Romani VC, BMC Cancer 2008, 8:373. [3] are linked to the cytoskeleton's intermediate Wong MP, Pathology 2008, 40:611-6. [4] filaments (e.g. cytokeratins, desmin, vimentin, Fukuoka J, Hum Pathol 2007, 38:276-83. [5] Schmitt CJ, J Invest Dermatol 2007, nestin). Expressed in most tissues tested and Sep;127(9):2191-206. [6] Li G, Oncogene. 2001 carcinomas. Calcium may be bound by the Dec 6;20(56):8125-35 cadherin-like repeats. Defects in DSG2 are the cause of familial arrhythmogenic right ventricular dysplasia 10 (ARVD10) [1]

ONC : Loss in desmogleins (desmosomal proteins of the cadherin family) is described in different tumor types, and is believed to promote cancer invasiveness [2-4]. In melanoma, desmogleins can be expressed but do not form desmosomes [5] and are downregulated by c-MET during progression [6] DSG3 Desmoglein 3, CDHF6 Desmocollin PHY : Component of intercellular desmosome [1] http://www.uniprot.org/uniprot/P32926. [2] junctions, which connect adjacent cells and Romani VC, BMC Cancer 2008, 8:373. [3] are linked to the cytoskeleton's intermediate Wong MP, Pathology 2008, 40:611-6. [4] filaments (e.g. cytokeratins, desmin, vimentin, Fukuoka J, Hum Pathol 2007, 38:276-83. [5] Schmitt CJ, J Invest Dermatol 2007, 127:2191- nestin). Expressed in epidermis, tongue, 206. [6] Li G, Oncogene 2001, 20:8125-35 tonsil, esophagus and carcinomas. Calcium may be bound by the cadherin-like repeats. Pemphigus vulgaris is a potentially lethal skin disease in which epidermal blisters occur as the result of the loss of cell-cell adhesion likely caused by autoantibodies against desmoglein-3 [1]

ONC : Loss in desmogleins (desmosomal

MMMP Biomap #87 Page 25 proteins of the cadherin family) is described in different tumor types, and is believed to promote cancer invasiveness [2-4]. In melanoma, desmogleins can be expressed but do not form desmosomes [5] and are downregulated by c-MET during progression [6] DSG4 Desmoglein 4, CDHF13 Desmocollin PHY : DSG4 (desmosomal protein of the [1] http://www.uniprot.org/uniprot/Q86SJ6 cadherin family) is highly expressed in skin, testis and prostate; less in salivary gland. In scalp follicles, present in the inner rooth sheath (IRS) and all layers of the matrix and precortex. Calcium may be bound by the cadherin-like repeats. Component of intercellular desmosome junctions. Involved in the interaction of plaque proteins and intermediate filaments mediating cell-cell adhesion. Coordinates the transition from proliferation to differentiation in hair follicle keratinocytes. Defects in DSG4 are the cause of localized autosomal hypotrichosis (LAH). DSG4 is one of the target molecules recognized by autoantibodies in patients with pemphigus vulgaris [1]

ONC : - Endomucin MUC14, EMCN ? PHY : Endothelial sialomucin that interferes [1] Matsubara A, J Exp Med 2005, 202:1483-92 with the assembly of focal adhesion complexes and inhibits interaction between cells and the extracellular matrix. Endothelial marker. marks hematopoietic stem cells throughout development [1]

ONC : - EPCAM Epithelial cell adhesion molecule, Ep- EPCAM PHY : This protein is expressed in almost all [1] Schmidt M, Clin Cancer Res 2008, 14:5849- CAM, MIC18, Ly74, TROP1, GA733-2, epithelial cell membranes but not on 55. [2] Gosens MJ, Mod Pathol 2007, 20:221- EGP34, EGP40, EGP-2, KSA, CD326, mesodermal or neural cell membranes. 32. [3] Tai KY, Oncogene 2007, 26:3989-97. [4] Ep-CAM, HEA125, KS1/4, MK-1, MH99, Mediates calcium-independent homotypic cell- Fong D, J Clin Pathol 2008, 61:31-5. [6] Winter MJ, Am J Pathol 2003, 163:2139-48. [7] MOC31, 323/A3, 17-1A, TACST-1 cell adhesions [6]. Upon (over-) expression of Baeuerle PA, Br J Cancer 2007, 96:417-23. [8] (tumor-associated calcium signal Ep-CAM, cadherin adhesions dissociate, Le Naour F, Front Biosci 2008, 13:5847-65 transducer 1), CO-17A, ESA which leads to accumulation of soluble E- cadherin/ beta-catenin complexes: this

MMMP Biomap #87 Page 26 suggests that during cell division, the strong E-cadherin-mediated cellular adhesion is abrogated, while the weaker intercellular adhesion mediated by Ep-CAM still holds the cell in place; after the proliferative phase, Ep- CAM expression declines and higher levels of E-cadherin mediate intercellular adhesions [6]

ONC : Ep-CAM overexpression is associated with poor survival in breast cancer [1]. However, loss of membranous Ep-CAM is associated with nuclear beta-catenin localization and contributes to reduced cell- cell adhesions, increased migratory potential and tumor budding in colon cancer [2]. Plus, forced expression of Ep-CAM decreases cancer invasiveness while silencing Ep-CAM expression enhances cancer invasiveness [3]. Is strongly expressed in a variety of epithelial cancers and represents a promising target for active (vaccination) and passive (e.g. anti- EPCAM antibody edrecolomab) anticancer immunotherapy [4]. Used as a pan-carcinoma marker [6] (e.g. for sorting/ detection of circulating tumor cells). Identified as one of the first tumor associated antigens, its role in cancer biology is being elucidated [7,8] ESAM Endothelial specific adhesion molecule, ESAM PHY : Likely mediates homophilic binding [1] Wegmann F, J Exp Med 2006, 203:1671-7. W117m activity. Involved in tight junction formation. [2] Clasper S, Cancer Res 2008, 68:7293-303. Supports neutrophil extravasation [1] [3] Ishida T, J Biol Chem 2003, 278:34598-604

ONC : Associated with tumor spread to lymphatics [2] also in melanoma [3] FAT1 Fat tumor suppressor homolog 1, ? PHY : Expressed in many epithelial and some [1] Tanoue T, J Cell Sci 2005, 118 (Pt 11):2347- CDHF7, Fat cadherin 1, endothelial and smooth muscle cells. Involved 53. [2] Willecke M, Curr Biol 2006, 16:2090-100. Fat 1 in cell-cell contacts (homophilic interaction ?) [3] Zeng Q, Cancer Cell 2008, 13:188-92. [4] and lamellipodial dynamics (by binding to Kwaepila N, Pathology 2006, 38:125-31 Ena/VASP proteins) [1]

ONC : Tumor suppressor gene in Drosophila, may act as a receptor of the Hippo signaling pathway [2] (a tumor suppressor pathway in

MMMP Biomap #87 Page 27 [3]). However, its over-expression and diffuse expression in both in situ and invasive carcinoma strongly suggests a role in breast carcinogenesis [4] FAT2 Fat tumor suppressor homolog 2, ? PHY : FAT2 mRNA is expressed in infant brain [1] Katoh Y, Int J Mol Med 2006, 18:523-8. [2] CDHF8, Fat cadherin 2, protocadherin and cerebellum [1] Matsui S, J Dermatol Sci 2008, 51:207-10 Fat 2 ONC : FAT2 mRNA is expressed in gastric cancer, pancreatic cancer, ovarian cancer, esophageal cancer, skin squamous cell carcinoma, head and neck cancer [1]. Knockdown of Fat2 by siRNA inhibits the migration of human squamous carcinoma cells FAT3 Fat tumor suppressor homolog 3, ? PHY : Expressed in embryonic stem cells, [1] Katoh Y, Int J Mol Med 2006, 18:523-8. [2] CDHF15, Fat cadherin 3, protocadherin primitive neuroectoderm, fetal brain, infant http://www.uniprot.org/uniprot/Q8TDW7 Fat 3 brain, adult neural tissues and prostate [1]. May play a role in the interactions between neurites derived from specific subsets of neurons during development [2]

ONC : - FAT4 Fat tumor suppressor homolog 4, ? PHY : Widely expressed. Expressed in fetal [1] Katoh Y, Int J Mol Med 2006, 18:523-8. [2] CDHF14, Fat cadherin 4, protocadherin and infant brain [1]. Fat4 regulates vertebrate Saburi S, Nat Genet 2008, 40:1010-5 Fat 4 planar cell polarity [2]

ONC : Expressed in brain tumor and colorectal cancer [1] GJA1 alpha 1 protein, - PHY : Expressed in the heart and fetal [1] http://www.uniprot.org/uniprot/P17302. [2] Li 43, CX43 (43 kDa) cochlea. May play a critical role in the Z, Clin Exp Metastasis 2008, 25:893-901. [3] physiology of hearing by participating in the Elzarrad MK, BMC Med 2008, 6:20. [4] Geng S, recycling of potassium to the cochlear Cell Biol Int 2007, 31:1420-7. [5] Zhang D, Cancer Lett 2007, 252:208-15. [6] Haass NK, J

MMMP Biomap #87 Page 28 CONNEXINS endolymph. Defects in GJA1 are the cause of Mol Histol 2004, 35:309-18. [7] Daniel-Wójcik A, oculodentodigital dysplasia (ODDD) and Int J Oncol 2008, 33:309-15. [8] Bertram JS, Biochim Biophys Acta 2005, 1740:170-8. [9] Connexons consist of six subunits, connexins. A connexon may be homomeric hypoplastic left heart syndrome (HLHS) [1] Mendoza-Naranjo A, J Immunol 2007, (i.e. composed of six identical connexin subunits) or heteromeric (i.e. including 178:6949-57 more than one species of connexins). Connexons associate end to end to form ONC : Conflicting data on the role of this a double-membrane gap junction channel. The channel may be homotypic connexin in cancer progression [2-5], although (identical connexons) or heterotypic (two different connexons). Gap junctions the majority of the reports are in favor of a mediate diffusion of low molecular weight from one cell to a neighboring cell and tumor suppressive activity (including in are involved in many physiological processes (e.g. electrical signal melanoma [6,7]). Is upregulated by cancer transmission) as well as in the genesis of diseases (e.g. cancer progression). preventing agents such as carotenoids and REFERENCES: [1] Evans WH, Biochem J 2006, 397:1-14. [2] Cronier L, retinoids [8]. Its expression on dendritic cells Antioxid Redox Signal 2009, 11:323-38 (DC) appears important for melanoma antigen cross-presentation [9]

GJA3 Gap junction alpha 3 protein, Connexin- Connexins PHY : Is a component of lens fiber gap [1] http://www.uniprot.org/uniprot/Q9Y6H8 46, CX46 (46 kDa) junctions. Defects in GJA3 are the cause of zonular pulverulent cataract type 3 (CZP3) [1]

ONC : - GJA4 Gap junction alpha 4 protein, Connexin- Connexins PHY : Expressed in multiple organs and [1] http://www.uniprot.org/uniprot/P35212 37, CX37 (37 kDa) tissues, including heart, uterus, ovary, and blood vessel endothelium [1]

ONC : - GJA5 Gap junction alpha 5 protein, Connexin- Connexins PHY: Defects in GJA5 are a cause of [1] http://www.uniprot.org/uniprot/P36382 40, CX40 (40 kDa) idiopathic atrial fibrillation [1]

ONC : - GJA8 Gap junction alpha 8 protein, Connexin- Connexins PHY : Expressed in eye lens. Defects in GJA8 [1] http://www.uniprot.org/uniprot/P48165 50, CX50 (50 kDa) are a cause of autosomal dominant congenital cataract [1]

ONC : - GJA9 Gap junction alpha 9 protein, Connexin- Connexins PHY : Highly abundant in skeletal muscle. Also [1] http://www.uniprot.org/uniprot/P57773 59, CX59 (59 kDa) detected in testis [1]

ONC : - GJA10 Gap junction alpha 10 protein, Connexin- Connexins PHY : Expressed in skeletal muscle and heart. [1] http://www.uniprot.org/uniprot/Q969M2 62, CX62 (62 kDa) Involved in tracer coupling between horizontal

MMMP Biomap #87 Page 29 cells of the retina [1]

ONC : - GJB1 Gap junction beta 1 protein, Connexin- Connexins PHY : Defects in GJB1 are the cause of [1] http://www.uniprot.org/uniprot/P08034. [2] 32, CX32 (32 kDa) Charcot-Marie-Tooth disease X-linked type 1 Hagiwara H, Br J Pharmacol 2008, 153:1373- (CMTX1), a form of Charcot-Marie-Tooth 81. [3] Sato H, Mol Carcinog 2007, 46:215-24 disease, the most common inherited disorder of the peripheral nervous system [1]

ONC : Demethylating agent 5-aza-CdR suppresses the growth of human renal cell carcinoma (RCC) in a xenograft model by restoring Cx32 expression [2]. Connexin 32 potentiates vinblastine-induced cytotoxicity in RCC cells [3] GJB2 Gap junction beta 2 protein, Connexin- Connexins PHY : Defects in GJB2 are a cause of non- [1] Ezumi K, Clin Cancer Res 2008, 14:677-84. 26, CX26 (26 kDa) syndromic sensorineural deafness [2] Naoi Y, Cancer Lett 2008, 262:248-56. [3] Nojima H, Curr Drug Saf 2007, 2:204-11. [4] Saito-Katsuragi M, Cancer 2007, 110:1162-72. ONC : Increased expression of GJB2 is [5] McLachlan E, Cancer Res 2006, 66:9886-94 associated with tumor progression in different models [1,2], including melanoma [3,4]. Opposite findings have also been reported [5] GJB3 Gap junction beta 3 protein, Connexin- Connexins PHY : Defects in GJB3 are a cause of [1] http://www.uniprot.org/uniprot/O75712 31, CX31 (31 kDa) erythrokeratodermia variabilis (EKV) and a cause of non-syndromic sensorineural deafness [1]

ONC : - GJB4 Gap junction beta 4 protein, Connexin- Connexins PHY : Defects in GJB4 are a cause of [1] http://www.uniprot.org/uniprot/Q9NTQ9 30.3, CX30.3 (30.3 kDa) erythrokeratodermia variabilis (EKV) [1]

ONC : - GJB5 Gap junction beta 5 protein, Connexin- Connexins PHY : ? - 31.1, CX31.1 (31.1 kDa) ONC : - GJB6 Gap junction beta 6 protein, Connexin- Connexins PHY : Defects in GJB6 are the cause of [1] Ozawa H, Anticancer Res 2007, 30, CX30 (30 kDa) ectodermal dysplasia type 2 (ED2) 27(4B):2189-95

ONC : Decreased expression of connexin 30 (and aberrant expression of connexin-26) in MMMP Biomap #87 Page 30 human head and neck cancer [1] GJB7 Gap junction beta 7 protein, Connexin- Connexins PHY : ? - 25, CX25 (25 kDa) ONC : - GJC1 Gap junction gamma 1 protein, Connexins PHY : ? - Connexin-45, CX45 (45 kDa) ONC : - GJC2 Gap junction gamma 2 protein, Connexins PHY : May play a role in myelination in central [1] http://www.uniprot.org/uniprot/Q5T442 Connexin-47, CX47 (47 kDa) and peripheral nervous systems. Defects in GJC2 are the cause of Pelizaeus-Merzbacher- like disease autosomal recessive type 1 (PMLD1), an autosomal recessive hypomyelinating leukodystrophy [1]

ONC : - GJC3 Gap junction gamma 3 protein, Connexins PHY : Mainly expressed in brain, spinal cord, [1] http://www.uniprot.org/uniprot/Q8NFK1 Connexin-30.2, CX30.2 (30.2 kDa) and sciatic nerve. Also expressed in skeletal muscle, liver and heart [1]

ONC : - GJD2 Gap junction delta 2 protein, Connexin- Connexins PHY : Highly expressed in neurons [1] [1] http://www.uniprot.org/uniprot/Q9UKL4 36, CX36 (36 kDa) ONC : - GJD3 Gap junction delta 3 protein, Connexin- Connexins PHY : Widely expressed [1] [1] http://www.uniprot.org/uniprot/Q8N144 31.9, CX31.9 (31.9 kDa) ONC : - GJD4 Gap junction delta 4 protein, Connexin- Connexins PHY : Widely expressed [1] [1] http://www.uniprot.org/uniprot/Q96KN9 40.1, CX40.1 (40.1 kDa) ONC : - GJE1 Gap junction epsilon 1 protein, Connexins PHY : ? - Connexin-23, CX23 (23 kDa) ONC : - HEPACAM Hepatocyte cell adhesion molecule, Fibronectin (?) PHY : Increases cell spreading on the matrices [1] Moh MC, J Biol Chem 2005, 280:27366-74. HEPN1, FLJ25530 fibronectin and matrigel, delays cell [2] Moh MC, J Hepatol 2003, 39:580-6. [3] Moh detachment, and enhances wound healing [1] MC, Carcinogenesis 2008, 29:2298-305

ONC : Downregulated in HCC [2]. Induces growth arrest via a p53/p21-dependent

MMMP Biomap #87 Page 31 pathway in human breast cancer cells [3] ICAM1 Intercellular adhesion molecule 1, CD54 ITG alpha L-beta2 PHY : Mainly expressed on endothelial cells. [1] Rahn JJ, Clin Exp Metastasis 2005, 22:475- Involved in leukocyte trans-endothelial 83. [2] Takahashi M, Clin Exp Metastasis 2008, migration. Interacts with MUC1 (expressed by 25:517-29. [3] Wang S, Int J Cancer 2006, epithelial cells). Is a Rhinovirus receptor 118:932-41. [4] Hamai A, Cancer Res 2008, 68:9854-64. [5] Weishaupt C, Clin Cancer Res 2007, 13:2549-56 ONC : Promotes the metastatic process of different cancer types [1,2] including melanoma [3,4]. Low expression of ICAM1 in melanoma specimens might underlie insufficient recruitment of cytotoxic T lymphocytes and thus limit the effectiveness of immunotherapy regimens [5] ICAM2 Intercellular adhesion molecule 2, CD102 ITG alpha L-beta2 PHY : Lymphocyte recirculation (by blocking [1] Tanaka H, Clin Cancer Res 2004, 10:4885- LFA-1-dependent cell adhesion). Adhesive 92. [2] Malero I, Cancer Res 2002, 62:3167-74 interactions important for antigen-specific immune response

ONC: Expressed on cancer cells, it enhances NK cell adhesion to and activation against them [1]. When expressed on endothelial cells inhibits dendritic cell based anticancer immune response [2] ICAM3 Intercellular adhesion molecule 3, CD50, ITG alpha L-beta2 PHY : Involved in leukocyte function [1] Kim YG, Cancer Lett 2006, 239:103-10. [2] ICAM-R, CDW50 ITG alpha D-beta2 Chung YM, Int J Cancer 2005, 117:194-201 ONC : Induces cancer cell proliferation through the PI3K/Akt pathway [1]. Associated with cancer resistance to radiotherapy [2] ICAM4 Intercellular adhesion molecule 4, CD242 ITG alpha L-beta2 PHY : Determines the Landsteiner-Wiener [1] Toivanen A, Biochim Biophys Acta 2008, ITG alpha4-beta1 blood group [1] 1780:456-66

ONC : - ICAM5 Intercellular adhesion molecule 5, ITG alpha L-beta2 PHY : Expressed by neurons of the [1] Gahmberg CG, Immunol Lett 2008, 117:131- Telencephalin ICAM5 telencephalon; regulation of immunological 5. [2] Tian L, Blood 2008, 111:3615-25 activity in the brain [1,2]

ONC : -

MMMP Biomap #87 Page 32 ITGA1 , CD49a Collagen PHY : Heterodimer with (VLA1, [1] Kikkawa Y, Exp Cell Res 2008, 314:2579-90. Laminin CD49a/CD29) [2] Brown MC, Int J Cancer 2008, 123:2195- 203. [3] Macias-Perez I, Cancer Res 2008, 68:6127-35 ONC : Modulates adhesion of hepatocellular carcinoma (HCC) cells to extracellular matrix (ECM) protein laminin alpha 5 [1] (laminins are a diverse group of alpha/beta/gamma

INTEGRINS (ITGs) heterotrimers formed from five alpha, three beta and three gamma chains). Obtustatin, a are alpha-beta heterodimeric receptors that connect the extracellular snake venom KTS-disintegrin, is a specific environment with intracellular signaling events. Integrins are important for inhibitor of this integrin and completely blocks normal development and function, but are also involved in the pathogenesis of cancer growth of MV3 human melanoma in diseases including cancer, autoimmunity and heart disease. Besides cell nude mice [2]. K-RAS and integrin alpha1- adhesion, integrins mediate cell signaling via activation of molecular cascades beta1 cooperate to drive the growth of non- such as those initiated by ILK (integrin linked kinase), FAK (focal adhesion small cell lung cancer (NSCLC) in vivo [3] kinase) and SFK (SRC family kinases) multifunctional intracellular effectors of cell-matrix interactions that regulates many cellular processes including growth, proliferation, survival, differentiation, migration, invasion and angiogenesis. REFERENCES: [1] McDonald PC, J Cell Sci. 2008 Oct 1;121(Pt 19):3121-32. [2] Guo W, Nat Rev Mol Cell Biol 2004, 5:816-26. [3] McCall-Culbreath KD, Curr Drug Targets. 2008 Feb;9(2):139-49

ITGA2 , CD49b Collagen PHY : Heterodimer with integrin beta 1 (VLA2, [1] Langsenlehner U, Breast Cancer Res Treat Laminin CD49b/CD29). It is responsible for adhesion 2006, 97:67-72. [2] Zhang Z, Blood 2008, Fibronectin of platelets and other cells to extracellular 111:1980-8. [3] Vuoristo M, Melanoma Res E-cadherin matrix (ECM) 2007, 17:215-23

ONC : Polymorphisms of this gene are associated with the risk of developing breast carcinoma [1]. VLA2 plays an important role in angiogenesis via regulation of VEGFR1 INTEGRIN HETERODIMERS expression: when challenged with B16F10 melanoma cells, mice lacking VLA2 For a synoptic view of all integrin heterodimers, please visit the dedicated MMMP expression exhibit increased tumor Biomap # 85 at the following address: angiogenesis associated with upregulated VEGFR1 expression [2]. High mRNA http://www.mmmp.org/MMMP/public/biomap/viewBiomap.mmmp?id=86 expression of integrin alpha2 is associated with poorer overall survival of melanoma patients [3]

ITGA2B , platelet glycoprotein IIb Fibrinogen PHY : Heterodimer with [1] http://www.uniprot.org/uniprot/P08514

MMMP Biomap #87 Page 33 (GP2B), CD41 Fibronectin (GPIIb/IIIa, CD41/CD61). Involved in platelet adhesion and aggregation (defects in ITGA2B Thrombospondin cause Glanzmann thrombasthenia). Von Willebrand factor Recognizes the sequence RGD in a wide array of ligands. Isoform-1 and isoform-2 are mainly expressed by platelets and megakaryocytes. Utilized as a platelet marker [1]

ONC : Isoform-3 is expressed by leukemia, prostate adenocarcinoma and melanoma cells but not by platelets or normal prostate or breast epithelial cells [1] ITGA3 , CD49c, VCA-2, GAPB3 Fibronectin PHY : Heterodimer with integrin beta 1 (VLA-3, [1] Fukushi J, Mol Biol Cell 2004, 15:3580-3590. (galactoprotein B3), MSK18 Collagen CD49c/CD29). May mediate with LGALS3 the [2] Katabami K, Clin Exp Metastasis 2005, Laminin stimulation by CSPG4 of endothelial cells 22:539-48. [3] Epiligrin migration [1]. Isoforms (3A and 3B) are http://www.uniprot.org/uniprot/P26006 Thrombospondin differentially expressed in tissues [3] CSPG4 ONC : The invasive and metastatic potential of hepatocellular carcinoma (HCC) are positively correlated with the expression level of integrin alpha3-beta1, whose expression is enhanced by transforming growth factor (TGF)beta-1 [2] ITGA4 , CD49d Fibronectin PHY : Heterodimer with integrin beta 1 (VLA-4, [1] Zhao J, Eur J Pharmacol 2008, 589:127-31. VCAM1 CD49d/CD29) and . On [2] Liang S, Am J Physiol Cell Physiol 2008, MadCAM1 activated endothelial cells, integrin VLA-4 295:C701-7. [3] Lee EJ, Int J Cancer 2008, triggers homotypic aggregation for most VLA- 123:2073-9. [4] Sasaki K, J Immunol 2008, 181:104-8 4-positive leukocyte cell lines. It may also participate in cytotoxic T-cell interactions with target cells

ONC : Gambogic acid downregulates ITGA4 expression and inhibits the adhesion and migration of B16-F10 melanoma cells in vitro and in vivo [1]. Integrin VLA-4 enhances sialyl- Lewisx/a-negative melanoma adhesion to and extravasation through the endothelium [2]. On the other hand, ITGA4 hypermethylation is associated with esophageal cancer recurrence [3]; plus, STAT6 signaling suppresses VLA-4 expression by CD8+ T cells and limits their

MMMP Biomap #87 Page 34 ability to infiltrate tumor lesions in vivo [4] ITGA5 , CD49e, FNRA Fibronectin PHY : Heterodimer with integrin beta 1 (VLA-5, [1] Huveneers S, Int J Radiat Biol 2007, (fibronectin receptor subunit alpha) Fibrinogen CD49e/CD29) [1]. It recognizes the sequence 83:743-51. [2] RGD in its ligands [2]. Promotes angiogenesis http://www.uniprot.org/uniprot/P08648. [3] Chen [5] Q, Int J Biochem Cell Biol 2008, 40:2164-73. [4] Bhaskar V, J Transl Med 2007, 5:61. [5] Kim S, Am J Pathol 2000, 156:1345-62. [6] Trochon- ONC : ADAM15 suppresses cell motility by Joseph V, Cancer Res 2004, 64:2062-9. [7] driving VLA-5 expression (via ERK Moyano JV, Mol Biol Cell 2003, 14:3699-715 inactivation) and reduces lung metastasis in a murine melanoma model [3]. VLA-4 promotes melanoma cell migration by inhibiting VLA-5 induced focal adhesions [7]. On the other side, VLA-5 blocking antibodies have anticancer activity in xenograft models [4] and ADAM15 recombinant disintegrin domain (RDD, which contains an RGD sequence and binds to both VLA-5 and integrin alphaV-beta3) has anticancer effect in an in vivo murine melanoma model [6]

ITGA6 , CD49f Laminin PHY : Heterodimer with integrin beta 1 (VLA-6, [1] http://www.uniprot.org/uniprot/P23229. [2] CD49f/CD29) or Liu L, J Biol Chem 2007, 282:31631-42. [3] (CD49f/CD104). Laminin receptor on platelets Hangan D, Cancer Res 1997, 57:3812-7. [4] (VLA-6) and epithelial cells (CD49f/CD104) Colomiere M, Int J Biochem Cell Biol 2008, Epub ahead of print. [5] Huang Y, Biochem [1]. Defects in ITGA6 are a cause of Biophys Res Commun 2008, 377:474-8. [6] epidermolysis bullosa with pyloric atresia Dutta U, Cancer Res 2008, 68:8779-87. [7] (EBPA) [1]. Tetraspanin CD151 promotes cell Tsuruta D, Curr Med Chem 2008, 15:1968-75 migration by regulating trafficking of integrins alpha3-beta1, alpha5-beta1 and alpha6-beta1 [2]

ONC : An epitope on VLA-6 involved in migration but not adhesion is required for extravasation of murine melanoma B16F1 MMMP Biomap #87 Page 35 cells in liver [3]. Neutralizing antibodies against alpha6 and beta1 subunits inhibit ovarian cancer cell migration [4]. Midkine promotes tetraspanin-VLA-6 interaction and induces FAK-STAT1alpha pathway contributing to migration/ invasiveness of human head&neck squamous cell carcinoma cells [5]. Expression of integrin alpha6-beta4 is associated with poor patient prognosis and reduced survival in a variety of human cancers and a key tyrosine (Y1494) in the beta4 integrin regulates multiple signaling pathways important for tumor development and progression [6]. Laminin-332-integrin (VLA-3 and alpha6-beta4) interaction is being investigated as a target for cancer therapy [7] ITGA7 , CD49g Laminin PHY : Heterodimer with integrin beta 1 [1] http://www.uniprot.org/uniprot/Q13683. [2] (CD49g/CD29). Originally identified in Ziober BL, Cell Growth Differ 1999, 10:479-90 melanoma, is the primary laminin receptor on skeletal myoblasts and adult myofibers. Defects in ITGA7 are associated with a form of congenital myopathy [1]

ONC : Expression of the alpha7-beta1 laminin receptor suppresses melanoma growth and metastatic potential [2] ITGA8 , CD49h Tenascin-C PHY : Heterodimer with integrin beta 1 [1] http://www.uniprot.org/uniprot/P53708 Fibronectin-1 (CD49h/CD29). Functions in the genesis of Vitronectin kidney and probably of other organs by Osteopontin regulating the recruitment of mesenchymal cells into epithelial structures; it recognizes the sequence RGD in a wide array of ligands [1]

ONC : - ITGA9 , Integrin alpha RLC VCAM1 PHY : Heterodimer with integrin beta 1. [1] http://www.uniprot.org/uniprot/Q13797. [2] Cytotactin Expressed in airway epithelium, basal layer of Bazan-Socha S, Biochemistry 2004, 43:1639- Osteopontin squamous epithelium, smooth muscle, 47. [3] Singh P, J Invest Dermatol 2009, Tenascin-C skeletal muscle and hepatocytes [1]. Three 129:217-28. [4] Staniszewska I, J Cell Sci 2008, 121(Pt 4):504-13. [5] Fiorilli P, Lab Invest 2008, NGF [4] non-RGD-containing disintegrins (VLO5, EO5 88:1143-56 and EC3) belong to the heterodimeric family of snake venom-derived proteins: they are potent inhibitors of certain leukocyte integrins such

MMMP Biomap #87 Page 36 as alpha4-beta1, alpha4-beta7, and alpha9- beta1. Loss of integrin alpha9-beta1 results in defects in proliferation, causing poor re- epithelialization during cutaneous wound healing [3]

ONC : Abundantly expressed in fetal lung and lung cancers [1]. Mediates adhesion of medulloblastoma cel ls to tenascin and activate pathways associated with survival and proliferation [5] ITGA10 Collagen PHY : Heterodimer with integrin beta 1. Widely [1] http://www.uniprot.org/uniprot/O75578. [2] expressed with highest expression in muscle Mirtti T, Int J Cancer 2006, 118:889-98 and heart [1]

ONC : Cell adhesion receptors, including the integrin-type collagen receptors (alpha1- beta1, alpha2-beta1, alpha10-beta1 and alpha11-beta1) participate in cancer progression and invasion. Quantitative RT- PCR indicated that all 4 receptors are abundantly expressed in sarcoma-derived cell lines, whereas most carcinoma-derived cells express alpha1-beta1 and alpha2-beta1 only [2] ITGA11 Collagen PHY : Heterodimer with integrin beta 1. [1] http://www.uniprot.org/uniprot/Q9UKX5. [2] Expressed in most tissues (low levels in Mirtti T, Int J Cancer 2006, 118:889-98 peripheral blood lymphocytes) [1]

ONC : Cell adhesion receptors, including the integrin-type collagen receptors (alpha1- beta1, alpha2-beta1, alpha10-beta1 and alpha11-beta1) participate in cancer progression and invasion. Quantitative RT- PCR indicated that all 4 receptors are abundantly expressed in sarcoma-derived cell lines, whereas most carcinoma-derived cells express alpha1beta1 and alpha2beta1 only [2] ITGAD , Leukointegrin alpha D, ICAM3 PHY : Heterodimer with . May [1] http://www.uniprot.org/uniprot/Q13349 ADB2, CD11d VCAM1 play a role in the atherosclerotic process such as clearing lipoproteins from plaques and in phagocytosis of blood-borne pathogens, MMMP Biomap #87 Page 37 particulate matter, and senescent erythrocytes from the blood [1]

ONC : - ITGAE Integrin alpha E, CD103, HML-1 (human E-cadherin PHY : Heterodimer with integrin beta 7. [1] http://www.uniprot.org/uniprot/P38570. [2] Le mucosal lymphocyte antigen 1) Mediates adhesion of intra-epithelial T- Floc'h A, J Exp Med 2007, 204:559-70 lymphocytes to epithelial cell monolayers (Expressed on a subclass of T-lymphocytes known as intra-epithelial lymphocytes which are located between mucosal epithelial cells) [1]

ONC : Interaction of epithelial cell marker E- cadherin (often lost during tumor progression)with integrin alpha E/beta7 (expressed by tumor-infiltrating lymphocytes, TIL) plays a major role in effective tumor cell lysis [2]; this integrin can be upregulated upon TCR engagement and by TGFb1 treatment, resulting in strong potentiation of antitumor lytic function [2] ITGAL , CD11a ICAM1 PHY : Heterodimer with integrin beta 2 (LFA-1, [1] http://www.uniprot.org/uniprot/P20701. [2] ICAM2 CD11a/CD18). Mainly expressed by Smith A, Immunol Rev 2007, 218:135-46. [3] ICAM3 leukocytes. Involved in a variety of immune Jenkinson SR, J Immunol 2005, 174:3401-7 ICAM4 phenomena including leukocyte-endothelial cell interaction, cytotoxic T-cell (CTL) mediated killing, and antibody dependent killing by granulocytes and monocytes [1]

ONC : LFA-1 is required for adequate immune response against cancer [2,3] ITGAM , CD11b, MAC-1 C3b PHY : Heterodimer with integrin beta 2 [1] http://www.uniprot.org/uniprot/P11215. [2] Fibrinogen (CD11b/CD18). Mainly expressed in Graf M, Am J Hematol 2006, 81:227-35 ICAM1 monocytes and granulocytes. Adhesion of monocytes, macrophages and granulocytes. Uptake of complement-coated particles (recognizes the RGD sequence in C3b) [1]

ONC : Expression of MAC-1 (CD11b) in acute myeloid leukemia (AML) is associated with an unfavorable prognosis [2]

MMMP Biomap #87 Page 38 ITGAV , CD51 Vitronectin PHY : Heterodimer with integrin beta 3 [1] Cai W, Anticancer Agents Med Chem 2006, Fibrinogen (CD51/CD61, VNR [vitronectin receptor]), 6:407-28. [2] Dayam R, J Med Chem 2006, Fibronectin , and integrin 49:4526-34. [3] Boswell CA, Mol Pharm 2008, Thrombospondin beta 8. Recognizes the RGD sequence in its 5:527-39. [4] Li X, J Cell Sci 2001, 114 (Pt 14):2665-72. [5] Reardon DA, Expert Opin Von Willebrand factor ligands. Investig Drugs 2008, 17:1225-35. [6] Gramoun Osteopontin A, J Cell Biochem 2007, 102:341-52. [7] Collagen ONC : CD51/CD61 plays a key role in Delbaldo C, Invest New Drugs 2008, 26:35-43. angiogenesis and tumor metastasis in many [8] Caswell PT, J Cell Biol 2008, 183:143-55. tumor models, including melanoma [4]. It is expressed on activated endothelial cells as well as some tumor cells but is not present in resting endothelial cells and most normal organ systems, which makes it a suitable target for anti-angiogenic cancer therapy [1,2,3] by means of different molecules such as RGD-containing peptides and antibodies, some of them being under clinical investigation (e.g. cilengitide [5], vitaxin [6], etaracizumab [7]). Of note, blocking the adhesive function of integrin alphaVbeta3 with soluble RGD ligands (e.g. osteopontin, cilengitide) promotes VLA-5 recycling and marked increase in fibronectin-dependent migration of tumor cells into 3D matrices [8]. ITGAX , CD11c, Leu M5 Fibrinogen PHY : Heterodimer with integrin beta 2 [1] http://www.uniprot.org/uniprot/P20702 (leukocyte adhesion receptor p150) (CD11c/CD18). Mediates cell-cell interaction during inflammatory responses; especially important in monocyte adhesion and chemotaxis [1]

ONC : - ITGB1 Integrin beta 1, CD29, GPIIA See integrins ITGA1 to PHY : Heterodimer with ITGA1, ITGA2, ITGA3, [1] Barkan D, Cancer Res 2008, 68:6241-50. [2] ITGA11 for details ITGA4, ITGA5, ITGA6, ITGA7, ITGA8, ITGA9, Brockbank EC, Br J Cancer 2005, 92:102-12. ITGA10, ITGA11. See these integrins for [3] Meyer S, J Invest Dermatol 2007, 127:1615- details 21

ONC : Signaling mediated by ITGB1 is believed to promote development and progression of cancer [1,2], including melanoma [3]. See integrins ITGA1 to ITGA11 for more details ITGB2 Integrin beta 2, CD18 See integrins ITGD, PHY : Heterodimer with ITGD, ITGM, ITGX. [1] http://www.uniprot.org/ uniprot/P05556 MMMP Biomap #87 Page 39 ITGM and ITGX for Beta-1 integrins recognize the sequence RGD details in a wide array of ligands. Involved in promoting endothelial cell motility and angiogenesis [1]. See these integrins for more details

ONC : See integrins ITGD, ITGM and ITGX for details ITGB3 Integrin beta 3, CD61, GPIIIa (platelet See integrins ITGA2B PHY : Heterodimer with ITGA2B and ITGAV. [1] http://www.uniprot.org/ uniprot/P05106. [2] glycoprotein IIIa) and ITGAV for details Phosphorylated on tyrosine residues in Müller DW, Oncogene 2008, 27:6698-706 response to thrombin-induced platelet aggregation [1]

ONC: ITGB3 is targeted by let-7 (a tumor suppressor microRNA) and promotes melanoma invasiveness [2]. See integrins ITGAV, ITGD, ITGM and ITGX for more details ITGB4 Integrin beta 4, CD104 Laminin PHY : Heterodimer with integrin alpha 6 [1] http://www.uniprot.org/uniprot/P23229. [2] (CD49f/CD104). Laminin receptor on Dutta U, Cancer Res 2008, 68:8779-87. [3] epithelial cells [1]. It plays a critical structural Tsuruta D, Curr Med Chem 2008, 15:1968-75 role in the hemidesmosome of epithelial cells [1]. Defects in ITGB4 are a cause of epidermolysis bullosa letalis with pyloric atresia (EBPA) [1]

ONC : Expression of integrin alpha6/beta4 is associated with poor patient prognosis and reduced survival in a variety of human cancers and a key tyrosine (Y1494) in the beta4 integrin regulates multiple signaling pathways important for tumor development and progression [2]. Laminin-332-integrin (VLA-3 and alpha6beta4) interaction is being investigated as a target for cancer therapy [3] ITGB5 Integrin beta 5 Fibronectin PHY : Heterodimer with integrin alpha V. It [1] http://www.uniprot.org/ uniprot/P18084 recognizes the sequence RGD in its ligand [1]

ONC : - ITGB6 Integrin beta 6 Fibronectin PHY : Heterodimer with integrin alpha V. It [1] http://www.uniprot.org/ uniprot/P18564. [2] Cytotactin recognizes the sequence RGD in its ligand [1]. Azare J, Mol Cell Biol 2007, 27:4444-53. [3] Ramos DM, Matrix Biol 2002, 21:297-307 MMMP Biomap #87 Page 40 Acts as a receptor for viruses such as foot- and-mouth disease virus (FMDV) and coxsackievirus [1]

ONC : Constitutively activated Stat3 induces tumorigenesis and enhances cell motility of prostate epithelial cells through integrin beta 6 [2]. Expression of integrin beta 6 enhances invasive behavior in oral squamous cell carcinoma [3] ITGB7 Integrin beta 7 E-cadherin PHY : Mainly expressed in leukocytes [1]. [1] http://www.uniprot.org/ uniprot/P26010 VCAM1 Integrin alpha-4/beta-7 (Peyer patches- MadCAM1 specific homing receptor LPAM-1) is an Fibronectin adhesion molecule that mediates lymphocyte migration and homing to gut-associated lymphoid tissue (GALT). Integrin alpha-4/beta- 7 interacts with the cell surface adhesion molecules MadCAM1 which is normally expressed by the vascular endothelium of the . Interacts also with VCAM1 and ECM component fibronectin. Binds to HIV-1 gp120, thereby allowing the virus to enter GALT, which is thought to be the major trigger of AIDS disease. Integrin alpha- E/beta-7 (HML-1) is a receptor for E-cadherin

ONC : - ITGB8 Fibronectin PHY : Heterodimer with integrin alpha V [1] [1] http://www.uniprot.org/ uniprot/P26012

ONC : - JAM1 F11R (), PAM-1 (platelet MPDZ PHY : Involved in tight junction assembly [1] Paschoud S, Mod Pathol 2007, 20:947-54. adhesion molecule), JCAM (junctional PARD3 (epithelial cells), endothelial cell function and [2] Martin TA, Cell Biol Int 2004, 28:361-71 cell adhesion molecule), JAMA, JAM-A, platelet adhesion to endothelium. Receptor CD321 for orthoreovirus

ONC : Decreased expression in lung squamous carcinoma [1]. In breast cancer HGF disrupts tight junctions by decreasing JAM1 expression [2] JAM2 Junctional adhesion molecule 2, VE-JAM JAM3 PHY : Involved in tight junction formation. [1] Ueki T, Microvasc Res 2008, 75:269-78. [2] (vascular endothelial JAM), JAM-B, Mainly expressed on high endothelial venules; Johnson-Léger CA, Blood 2002, 100:2479-86

MMMP Biomap #87 Page 41 JAMB, CD322 plays a role in lymphocyte homing to secondary lymphoid organs [1,2]

ONC : - JAM3 Junctional adhesion molecule 3, JAM-C, JAM2 PHY : Involved in tight junction formation. [1] Ueki T, Microvasc Res 2008, 75:269-78. [2] JAMC Promotes neutrophil transendothelial Chavakis T, J Biol Chem 2004, 279:55602-8 migration. Participates in cell-cell adhesion distinct from tight junctions [1,2]

ONC : - L1CAM cell adhesion molecule, NCAM-L1, -1 PHY : Defects in L1CAM cause hydrocephalus [1] Issa Y, J Mol Med 2008, Epub ahead of print. CD171 Integrins or other nervous system diseases [2] Gast D, Oncogene 2008, 27:1281-9. [3] Meier F, Int J Cancer 2006, 119:549-55 ONC : Expression on tumor endothelium mediates selective tumor cell transmigration [1]. Promotes invasiveness of different tumors including melanoma [3], at least in part through ERK stimulation LAMP1 Lysosomal associated membrane protein Selectins PHY : Presents carbohydrate ligands to [1] http://www.uniprot.org/uniprot/P11279. [2] 1, CD107a selectins [1]. Translocated to the cell surface Kannan K, Cell Immunol 1996, 171:10-9. [3] upon activation. Glycoprotein in human Künzli BM, Cancer 2002, 94:228-39 peripheral blood mononuclear cells that mediates cell adhesion to vascular endothelium [2]. Also involved in lysosome/ endosome activities

ONC : Can be expressed by malignant cells, is a ligand of -3 and may influence tumor proliferation and metastasis formation [3] LAMP2 Lysosomal associated membrane protein Selectins PHY : Presents carbohydrate ligands to [1] http://www.uniprot.org/uniprot/P13473. [2] 2, CD107b selectins [1]. Translocated to the cell surface Kannan K, Cell Immunol 1996, 171:10-9. [3] upon activation. Glycoprotein in human Künzli BM, Cancer 2002, 94:228-39 peripheral blood mononuclear cells that mediates cell adhesion to vascular endothelium [2]. Also involved in lysosome/ endosome activities

ONC : Can be expressed by malignant cells, is a ligand of galectin-3 and may influence tumor proliferation and metastasis formation

MMMP Biomap #87 Page 42 [3] MADCAM1 Mucosal vascular addressin cell ITG alpha4-beta7 PHY : Cell adhesion leukocyte receptor [1] Nummer D, J Natl Cancer Inst 2007, adhesion molecule 1, MACAM1 L-selectin expressed by mucosal venules (lymphocyte 99:1188-99 traffic into mucosal tissues, e.g. Peyer patches, intestinal lamina propria during inflammation)

ONC : Tumor-induced expression of addressins on the surface of endothelial cells allows a selective transmigration of Treg cells from peripheral blood to tumor tissues MCAM Melanoma cell adhesion molecule, MCAM PHY : Cohesion of endothelial cells at [1] Wu GJ, Mol Cancer Res 2008, 6:1666-77. [2] MUC18, CD146 intercellular junctions. Surface receptor Staquicini FI, Cancer Res 2008, 68:8419-28. [3] triggering tyrosine phosphorylation of FYN and Rapanotti MC, Br J Dermatol 2008, Epub ahead PTK2. Detected in endothelial cells in vascular of print tissue throughout the body

ONC : Promotes invasiveness and in vivo metastasis of melanoma cells [1,2]. Associated with advanced stages in melanoma patients [3]. May allow melanoma cells to interact with cellular elements of the vascular system, thereby enhancing hematogenous tumor spread MTDH Metadherin, LYRIC, AEG-1 (astrocyte ? PHY : Tight junction protein [1] Hu G, Cancer Cell 2009, 15:9-20. [2] Brown elevated gene 1) DM, Cancer Cell 2004, 5:365-74. [3] Sarkar D, Cancer Res 2008, 68:1478-84. [4] Lee SG, ONC : Overexpressed in more than 40% of Oncogene 2008, 27:1114-21. [5] Kikuno N, breast cancers, associated with poor clinical Oncogene 2007, 26:7647-55. [6] Emdad L, outcomes; activation by 8q22 genomic gain Cancer Res 2006, 66:1509-16 promotes chemoresistance and metastasis of poor-prognosis breast cancer [1,2]. promote tumor cell migration and invasion through activation of NFkB [3] and survival through PI3K/AKT stimulation [4] and FOXO3a inhibition [5]. AEG-1 expression is elevated also in subsets of melanoma cells [6] MUC1 1, Episialin, CD227, PUM, PEM ICAM PHY : Acts as a heterodimeric complex of two [1] http://www.uniprot.org/uniprot/P15941. [2] subunits, MUC1-alpha and MUC1-beta, Singh R, Cancer Biol Ther 2007, 6:481-6. [3] Tang CK, Expert Rev Vaccines 2008, 7:963-75

MMMP Biomap #87 Page 43 derived from a single gene. Involved in epithelial cell adhesion, may provide a Mucins are high-molecular weight epithelial glycoproteins with a high content of protective layer on epithelial cells. Modulates clustered oligosaccharides O-glycosidically linked to tandem repeat peptides signaling in ERK, SRC and NFkB pathways. rich in threonine, serine, and proline. There are two structurally and functionally Forms a MUC1/GRB2/SOS1 complex distinct classes of mucins: secreted gel-forming mucins (MUC2, MUC5AC, involved in RAS signaling. Binds, together with MUC5B, and MUC6) and transmembrane mucins (MUC1, MUC3A, MUC3B, KLF4, the PE21 promoter element of P53 and MUC4, MUC12, MUC17), although the products of some MUC genes do not fit represses P53 activity. The cytoplasmic tail well into either class (MUC7, MUC8, MUC9, MUC13, MUC15, MUC16). interacts with several proteins such as SRC, Deregulation of mucin expression and or can be found in many CTNNB1 and ERB family members. tumor types. The O-glycosidically linked oligosaccharides of mucins can be Interaction with the SH2 domain of CSK described in terms of core type (e.g. Tn antigen [GalNAcalphaThr/Ser], TF decreases interaction with GSK3B. Interacts antigen [Galbeta3GalNAc], sialyl Tn [NeuAcalpha6GalNAc]), backbone type, with CTNNB1/beta-catenin and JUP/gamma- and peripheral structures. Cancer-related mucins differ from those of healthy catenin and promotes cell adhesion. tissues mainly in core and peripheral carbohydrate structures, which are being Interaction with JUP/gamma-catenin is investigated as diagnostic and prognostic markers, as well as targets for induced by heregulin. Binds PRKCD, ERBB2, immunotherapy. core structures:. REFERENCES: [1] Carraway KL, Curr Top ERBB3 and ERBB4. Heregulin (HRG) Dev Biol 2007, 78:1-22. [2] Singh AP, Lancet Oncol 2008, 9:1076-85. [3] stimulates the interaction with ERBB2 and, to Yonezawa S, Proteomics 2008, 8:3329-41 a much lesser extent, the interaction with ERBB3 and ERBB4 [1]

ONC : Overexpressed in adenocarcinomas and hematological cancers [2]. Interaction, via the tandem repeat region, with domain 1 of ICAM1 is implicated in carcinoma cell migration and metastasis [1]. Is being

MMMP Biomap #87 Page 44 evaluated as tumor antigen for anticancer immunotherapy [3]

MUC2 ? PHY : Secreted glycoprotein. Coats the [1] http://www.uniprot.org/uniprot/Q02817 epithelia of the intestines, airways, and other membrane-containing organs. Thought to provide a protective, lubricating barrier against particles and infectious agents at mucosal surfaces [1]

ONC : - MUC3A ? PHY : See MUC2 -

ONC : - MUC3B Mucin 3B ? PHY : See MUC2 -

ONC : -

MMMP Biomap #87 Page 45 MUC4 ? PHY : A heterodimeric complex of two [1] Bafna S, Cancer Res 2008, 68:9231-8. [2] subunits, ASGP-1 and ASGP-2, derived from Ponnusamy MP, Br J Cancer 2008, 99:520-6. a single gene. It is produced by multiple [3] Chaturvedi P, Cancer Res 2008, 68:2065-70. epithelia in both membrane and soluble forms [4] Chaturvedi P, FASEB J 2008, 22:966-81 and serves as a protective agent for the epithelia Expressed in the thymus, thyroid, lung, , esophagus, stomach, small intestine, colon, testis, prostate, ovary, uterus, placenta, and mammary and salivary glands

ONC : Ability to promote tumor growth may be mainly due to repression of apoptosis as opposed to proliferation. Seems to alter cellular behavior through both anti-adhesive effects on cell-cell and cell-extracellular matrix interactions and in its ability to act as an intramembrane ligand for ErbB2 (through its EGF-like domains). The transmembrane subunit ASGP-2 acts as an intramembrane ligand and activator for the receptor tyrosine kinase ErbB2. Formation of this ligand- receptor complex is proposed to repress apoptosis in epithelial and cancer cells MUC5AC Mucin 5AC ? PHY : See MUC2 -

ONC : - MUC5B ? PHY : See MUC2 -

ONC : - MUC6 ? PHY : See MUC2 -

ONC : - MUC7 ? PHY : See MUC2 -

ONC : - MUC12 Mucin 12 ? PHY : Involved in epithelial cell protection, [1] http://www.uniprot.org/uniprot/Q9UKN1 adhesion modulation, and signaling. May be involved in epithelial cell growth regulation. Stimulated by both cytokine TNF-alpha and TGF-beta in intestinal epithelium. Ubiquitous,

MMMP Biomap #87 Page 46 with higher expression in colon [1]

ONC : - MUC13 Mucin 13 ? PHY : ? -

ONC : - MUC15 Mucin 15 ? PHY : May play a role in the cell adhesion to [1] http://www.uniprot.org/uniprot/Q8N387. [2] the extracellular matrix [1] Riker AI, BMC Med Genomics 2008, 1:13

ONC : Downregulated in metastatic as compared to primary melanoma [2] MUC16 Mucin 16, CA125 Mesothelin PHY : Thought to provide a protective, [1] http://www.uniprot.org/uniprot/Q8WXI7 lubricating barrier against particles and infectious agents at mucosal surfaces. Binding to MSLN (mesothelin) mediates heterotypic cell adhesion. May be secreted into the extracellular space following the phosphorylation of the intracellular C-terminus which induces the proteolytic cleavage of the extracellular domain. Expressed in corneal and conjunctival epithelia [1]

ONC : Overexpressed in ovarian cancer (is used in the clinical practice as a serum marker). Interaction with MSLN (normally expressed by mesothelial cells) likely explains ovarian cancer tropism for peritoneum. MUC17 ? PHY : Expressed almost exclusively in the [1] http://www.uniprot.org/uniprot/Q685J3 intestine. Probably plays a role in maintaining homeostasis on mucosal surfaces [1]

ONC : Highly expressed in pancreatic adenocarcinoma tissue (at protein level). Expression is not detectable in normal pancreas, in pancreatitis or in cell lines derived from other cancers [1] MUC19 Mucin 19 ? PHY : Expressed corneal epithelial cells, [1] http://www.uniprot.org/uniprot/Q7Z5P9 conjunctival goblet and epithelial cells and lacrimal gland cells, may function in ocular

MMMP Biomap #87 Page 47 mucus homeostasis [1]

ONC : - MUC20 ? PHY : Highly expressed in kidney, moderately [1] Higuchi T, Mol Cell Biol 2004, 24:7456-68 in placenta, lung, prostate, liver, and digestive system. May regulate c-MET signaling cascade by decreasing hepatocyte growth factor (HGF)-induced transient MAPK activation; blocks GRB2 recruitment to c-MET thus suppressing the GRB2-RAS pathway; inhibits HGF-induced proliferation of MMP1 and MMP9 expression [1]. Oligomerization is required for interaction with c-MET

ONC : - MUC21 Mucin 21, Epiglycanin ? PHY : Expressed in lung, , [1] Itoh Y, Glycobiology 2008, 18:74-83 thymus, and testis. Expressed in normal and malignant bronchial epithelial cells

ONC : Could be a marker of lung adenocarcinoma [1] MUPCDH Mucin-like protocadherin, MUCDHL ? PHY : Acts as a calcium-dependent cell [1] http://www.uniprot.org/uniprot/Q9HBB8 adhesion protein. Highest expression in kidney, liver, colon and small intestine [1]

ONC : - NCAM1 Neural cell adhesion molecule 1, NCAM, NCAM1 PHY : Involved in neuron-neuron adhesion, [1] Zecchini S, Neurochem Res 2008, Epub CD56 neurite fasciculation and outgrowth of ahead of print neurites. First described in neurons, is also expressed in a wide variety of non-neuronal cell types

ONC : Expression is deregulated in different cancer types. However, NCAM can exert both a positive and a negative effect on cancer progression depending on the tumor context [1] NCAM2 Neural cell adhesion molecule 2, NCAM2 PHY : Expressed most strongly in adult and [1] Kulahin N, Neurochem Res 2008, Epub NCAM21, N-CAM2, OCAM (olfactory fetal brain. May play important roles in ahead of print CAM), RNCAM selective fasciculation and zone-to-zone

MMMP Biomap #87 Page 48 projection of the primary olfactory axons [1]

ONC : - 1 PVRL1 (poliovirus receptor related 1), PHY : Promotes cell-cell contacts by forming [1] Takai Y, Nat Rev Mol Cell Biol 2008, 9:603- HVEC (Herpes virus entry mediator C), homophilic or heterophilic trans-dimers. 15. [2] Yu Z, Cancer Gene Ther 2007, 14:738- CD111 Heterophilic interactions: can form trans- 47 heterodimers with PVRL3/nectin-3 and with PVRL4/nectin-4 [1]

ONC : Calcium depletion enhances nectin-1 expression and herpes oncolytic therapy of squamous cell carcinoma [2] Nectin 2 PVRL2 (poliovirus receptor related 2), Nectins PHY : Can form trans-heterodimers with [1] http://www.uniprot.org/uniprot/Q92692 CD112 PVRL3/nectin-3. Interacts with CD226. Receptor for alpha herpesvirus (HSV-1, HSV- 2 and pseudorabies virus) entry into cells

ONC : - Nectin 3 PVRL3 (poliovirus receptor related 3), Nectins PHY : Plays a role in cell-cell adhesion through [1] http://www.uniprot.org/uniprot/Q9NQS3 CD113 heterophilic trans-interactions with nectin-like proteins or nectins, such as trans-interaction with PVRL2/nectin-2 at Sertoli-spermatid junctions. Cis- and trans-homodimer. Can form trans-heterodimers with PVRL1/nectin-1 and PVRL2/nectin-2 [1]

ONC : - Nectin 4 PVRL4 (poliovirus receptor related 4) Nectins PHY : Seems to be involved in cell adhesion [1] http://www.uniprot.org/uniprot/Q96NY8. [2] through trans-homophilic and -heterophilic Fabre-Lafay S, BMC Cancer 2007, 7:73 interactions, the latter including specifically interactions with PVRL2/nectin-1

ONC : Nectin-4 is a new histological and serological tumor associated marker for breast cancer [2] NRCAM NgCAM related cell adhesion molecule, NRCAM PHY : Mainly expressed in central nervous [1] Grumet M, Cell Tissue Res 1997, 290:423-8. Nr-CAM, Bravo Neurofascin system (CNS). Cell adhesion, ankyrin-binding [2] Chen D, Cancer Res 2003, 63:6626-34. [3] RPTPbeta [1] protein involved in neuron-neuron adhesion Conacci-Sorrell ME, Genes Dev 2002, 16:2058- 72. [4] Conacci-Sorrell M, Cancer Res 2005, 65:11605-12 ONC : Is a target of SKI (inhibitor of TGF-beta

MMMP Biomap #87 Page 49 pathway and stimulator of WNT/beta-catenin pathway) [2] and is associated with melanoma cell survival, growth, motility and transformation [3]. Metalloprotease-mediated shedding of NRCAM is a route for NRCAM mediated oncogenesis [4] Occludin OCLN TJP1 PHY : Plays a role in the formation and [1] http://www.uniprot.org/uniprot/Q16625. [2] regulation of the tight junction paracellular Harten SK, Mol Biol Cell 2008, Epub ahead of permeability barrier. Can induce adhesion print. [3] Osanai M, Cancer Sci 2007, 98:1027- when expressed in cells lacking tight 34 junctions. Localized at tight junctions of both epithelial and endothelial cells. Highly expressed in kidney [1]

ONC : In renal cell carcinoma (RCC), VHL loss leads to epithelial mesenchymal transition (EMT) by downregulation not only of E- cadherin expression (adherens junction) but also occludin and claudin-1 (tight junction) [2]. Occludin-mediated premature senescence is a fail-safe mechanism against tumorigenesis in breast carcinoma cells [3] OMD Osteomodulin, Osteoadherin ITG alpha V-beta3 PHY : May be implicated in biomineralization [1] http://www.uniprot.org/uniprot/Q99983 processes. Has a function in binding of osteoblasts via integrin alpha V-beta 3

ONC : - OPCML Opioid binding protein/cell adhesion Opioids PHY : Belongs to the IgLON (OPCML, LSAMP, [1] Lodge AP, Brain Res Mol Brain Res 2000, molecule-like, OPCM, OBCAM (opioid OPCML NEGR1 and HNT) family of glycosyl 82:84-94. [2] Cui Y, PLoS ONE 2008, 3:e2990. binding cell adhesion molecule) LSAMP [1] phosphatidyl inositol (GPI)-anchored cell [3] Mei FC, FASEB J 2006, 20:497-9 adhesion molecules (CAM) that are highly expressed in the nervous system

ONC : Is considered a tumor suppressor for multiple carcinomas and lymphomas with frequently epigenetic inactivation [2,3]. Ectopic expression leads to inhibition of both anchorage-dependent and -independent growth of carcinoma cells [2]

MMMP Biomap #87 Page 50 PCDH1 Protocadherin 1, PC42 ? PHY : May be involved in cell-cell interaction [1] http://www.uniprot.org/uniprot/Q08174. [2] processes and in cell adhesion. Highly Redies C, Cell Mol Life Sci 2005, 62:2840-52 expressed in the brain and neuro-glial cells. Highest expression in adults [1]. Belongs to the delta-protocadherins that comprise

PROTOCADHERINS (PCDHs) PCDH7, PCDH8, PCDH9, PCDH10, PCDH11, PCDH17, PCDH18, PCDH19, PCDHX and Protocadherins are the largest subgroup within the cadherin superfamily, PCDHY [2] usually contain 6 to 7 cadherin repeats in their extracellular domain, are predominantly expressed in the nervous system, lack an interface for homophilic adhesiveness (found in classical cadherins) and present loop ONC : - structures absent in other members of the cadherin superfamily. They are involved in both cell adhesion and cell signaling. REFERENCES: [1] Morishita H, Curr Opin Cell Biol 2007, 19:584-92. [2] Takeichi M, Nat Rev Neurosci 2007, 8:11-20

PCDH7 Protocadherin 7, BH-PCDH (brain heart) ? PHY : Expressed predominantly in brain and [1] http://www.uniprot.org/uniprot/O60245. [2] heart and at lower levels in various other Singh AP, Cancer Lett 2008, 259:28-38 tissues [1]

ONC : Upregulated in androgene independent prostate carcinoma [2] PCDH8 Protocadherin 8, PAPC, ARCADLIN ? PHY : Potential calcium-dependent cell- [1] Yu JS, Oncogene 2008, 27:4657-65 adhesion protein

ONC : Candidate tumor suppressor of breast cancer [1] PCDH9 Protocadherin 9 ? PHY : Potential calcium-dependent cell- [1] de Tayrac M, Genes Cancer adhesion protein 2009, 48:55-68

ONC : Candidate tumor suppressor gene of glioblastoma [1] PCDH10 Protocadherin 10, Protocadherin-OL ? PHY : Potential calcium-dependent cell- [1] http://www.uniprot.org/uniprot/Q9P2E7. [2] adhesion protein. Moderately expressed in all Yu J, Gastroenterology 2008, Epub ahead of regions of the brain examined, as well as in print. [3] Ying J, Oncogene 2006, 25:1070-80. testis and ovary, and low expression in all [4] Ying J, Br J Haematol 2007, 136:829-32 other tissues tested [1]

ONC : Tumor suppressor gene whose methylation is associated with poor prognosis

MMMP Biomap #87 Page 51 in patients with gastric cancer [2]. Epigenetically silenced (by methylation) also in other carcinomas and multiple hematologic malignancies [4] PCDH11X Protocadherin 11 X- linked, PCDHX, ? PHY : Potential calcium-dependent cell- [1] http://www.uniprot.org/uniprot/Q9BZA7 Protocadherin-S adhesion protein. Expressed strongly in fetal brain and brain (cortex, amygdala, thalamus, substantia nigra, hippocampus, caudate nucleus and corpus callosum) [1]

ONC : - PCDH11Y Protocadherin 11 Y- linked, PCDHY, ? PHY : Potential calcium-dependent cell- [1] http://www.uniprot.org/uniprot/Q9BZA8 PCDH-PC (prostate cancer) adhesion protein. Interacts with CTNNB1. Expressed strongly in fetal brain and brain (cortex, amygdala, thalamus, substantia nigra, hippocampus, caudate nucleus and corpus callosum). Expressed in apoptosis-resistant cells. A chromosomal aberration involving PCDH11Y is a cause of multiple congenital abnormalities including severe bilateral vesico-ureteral reflux [1]

ONC : - PCDH12 Protocadherin 12, VE-cadherin 2 ? PHY: Expressed in highly vascularized tissues [1] Rampon C, Physiol Genomics 2008, 34:193- including the heart and placenta, but most 204. [2] http://www.uniprot.org/uniprot/Q9NPG4 tissues contain a low level of expression. Prominent expression in the spleen. Cellular adhesion molecule that may play an important role in cell-cell interactions at interendothelial junctions. Promotes homotypic calcium dependent aggregation and adhesion and clusters at intercellular junctions. Unable to bind to catenins, weakly associates with the cytoskeleton [1,2]

ONC : - PCDH15 Protocadherin 15, DFNB23 ? PHY : Calcium-dependent cell-adhesion [1] http://www.uniprot.org/uniprot/Q96QU1. [2] protein. Expressed in brain, lung, kidney, Rouget-Quermalet V, Oncogene 2006, 25:2807- spleen and testis. Essential for maintenance 11 of normal retinal and cochlear function. Defects in PCDH15 are the cause of Usher

MMMP Biomap #87 Page 52 syndrome type 1F (USH1F, association of retinitis pigmentosa and sensorineural deafness) and DFNB23 (non-syndromic sensorineural deafness recessive type 23) [1]

ONC : whereas protocadherins are absent from the surface of normal hematopoietic cells, we describe, for the first time, that PCDH15 is expressed in cytotoxic tumor- derived T- and NK-cell lines as well as in biopsies of nasal NK/T-cell lymphomas [2] PCDH17 Protocadherin 17, PCDH68 ? PHY : Potential calcium-dependent cell- [1] http://www.uniprot.org/uniprot/O14917 adhesion protein [1]

ONC : - PCDH18 Protocadherin 18, PCDH68L ? PHY : Potential calcium-dependent cell- [1] http://www.uniprot.org/uniprot/Q9HCL0 adhesion protein. Expressed in all tissues, with highest expression in lung and ovary [1]

ONC : - PCDH19 Protocadherin 19 ? PHY : Potential calcium-dependent cell- [1] http://www.uniprot.org/uniprot/Q8TAB3. [2] adhesion protein. Moderately expressed in all Dibbens LM, Nat Genet 2008, 40:776-81 regions of the brain examined, with lowest levels found in the cerebellum. Moderate expression is also found in ovary, and low expression in all other tissues tested. Also detected in primary skin fibroblast. Defects in PCDH19 are the cause of epilepsy, female- restricted, with mental retardation (EFMR) [1,2]

ONC : - PCDH20 Protocadherin 20, PCDH13 ? PHY : Potential calcium-dependent cell- [1] Imoto I, Cancer Res 2006, 66:4617-26 adhesion protein

ONC : Candidate tumor suppressor gene frequently silenced by epigenetic mechanism (promoter hypermethylation) in non-small-cell lung cancer (NSCLC); its methylation status correlates with patients survival [1] PCDH21 Protocadherin 21, PR-cadherin ? PHY : Potential calcium-dependent cell- [1] http://www.uniprot.org/uniprot/Q96JP9. [2] MMMP Biomap #87 Page 53 (photoreceptor) adhesion protein. May be required for the Bolz H, Mol Vis 2005, 11:929-33 structural integrity of the outer segment of photoreceptor cells [1]. Candidate gene for human retinal dystrophies [2]

ONC : - PCDH24 Protocadherin 24, PCDH LKC (liver ? PHY : Role in contact inhibition at the lateral [1] http://www.uniprot.org/uniprot/Q9BYE9. [2] kidney colon) surface of epithelial cells. Highly expressed in Okazaki N, Carcinogenesis 2002, 23:1139-48 liver, kidney and colon [1]

ONC : Downregulated in liver and colon cancers [2], where it acts as a tumor suppressor gene by mediating contact inhibition [2] PCDHA1 Protocadherin alpha 1 ? PHY : Potential calcium-dependent cell- [1] http://www.uniprot.org/uniprot/Q9Y5I3. [2] adhesion protein. May be involved in the Hirayama T, Curr Opin Neurobiol 2006, 16:336- establishment and maintenance of specific 42. [3] Novak P, Cancer Res 2008, 68:8616-25 neuronal connections in the brain [1]. Belongs to the clustered protocadherin subfamily of the cadherin superfamily. Clustered PCDH are predominantly expressed in the nervous system and are substructured into three distinct gene arrays in mammals: Pcdh-alpha, Pcdh-beta, and Pcdh-gamma. Pcdh-alpha proteins interact with ITGB1 to promote cell adhesion [2]

ONC : Changes in DNA methylation patterns are a common characteristic of cancer cells; recent studies suggest that DNA methylation affects not only discrete genes, but it can also affect large chromosomal regions potentially leading to LRES ( long-range epigenetic events); in breast carcinoma, one example of a newly discovered agglomerate of hypermethylated regions associated with gene silencing involves the protocadherin gene family clusters on 5 (PCDHA, PCDHB, and PCDHG) [3] PCDHA2 Protocadherin alpha 2 ? PHY : See PCDHA1 for details [1] http://www.uniprot.org/uniprot/Q9Y5H9

ONC : See PCDHA1 for details MMMP Biomap #87 Page 54 PCDHA3 Protocadherin alpha 3 ? PHY : See PCDHA1 for details [1] http://www.uniprot.org/uniprot/Q9Y5H8

ONC : See PCDHA1 for details PCDHA4 Protocadherin alpha 4, CNR1 ? PHY : See PCDHA1 for details [1] http://www.uniprot.org/uniprot/Q9UN74

ONC : See PCDHA1 for details PCDHA5 Protocadherin alpha 5, CNR6 ? PHY : See PCDHA1 for details [1] http://www.uniprot.org/uniprot/Q9Y5H7

ONC : See PCDHA1 for details PCDHA6 Protocadherin alpha 6, CNR2 ? PHY : See PCDHA1 for details [1] http://www.uniprot.org/uniprot/Q9UN73

ONC : See PCDHA1 for details PCDHA7 Protocadherin alpha 7, CNR4 ? PHY : See PCDHA1 for details [1] http://www.uniprot.org/uniprot/Q9UN72

ONC : See PCDHA1 for details PCDHA8 Protocadherin alpha 8 ? PHY : See PCDHA1 for details [1] http://www.uniprot.org/uniprot/Q9Y5H6

ONC : See PCDHA1 for details PCDHA9 Protocadherin alpha 9 ? PHY : See PCDHA1 for details [1] http://www.uniprot.org/uniprot/Q9Y5H5

ONC : See PCDHA1 for details PCDHA10 Protocadherin alpha 10, CNR8 ? PHY : See PCDHA1 for details [1] http://www.uniprot.org/uniprot/Q9Y5I2

ONC : See PCDHA1 for details PCDHA11 Protocadherin alpha 11, CNR7 ? PHY : See PCDHA1 for details [1] http://www.uniprot.org/uniprot/Q9Y5I1

ONC : See PCDHA1 for details PCDHA12 Protocadherin alpha 12 ? PHY : See PCDHA1 for details [1] http://www.uniprot.org/uniprot/Q9UN75

ONC : See PCDHA1 for details PCDHA13 Protocadherin alpha 13, CNR5 ? PHY : See PCDHA1 for details [1] http://www.uniprot.org/uniprot/Q9Y5I0

ONC : See PCDHA1 for details PCDHB1 Protocadherin beta 1 ? PHY : See PCDHA1 for details [1] http://www.uniprot.org/uniprot/Q9Y5F3

ONC : See PCDHA1 for details

MMMP Biomap #87 Page 55 PCDHB2 Protocadherin beta 2 ? PHY : See PCDHA1 for details [1] http://www.uniprot.org/uniprot/Q9Y5E7

ONC : See PCDHA1 for details PCDHB3 Protocadherin beta 3 ? PHY : See PCDHA1 for details [1] http://www.uniprot.org/uniprot/Q9Y5E6

ONC : See PCDHA1 for details PCDHB4 Protocadherin beta 4 ? PHY : See PCDHA1 for details [1] http://www.uniprot.org/uniprot/Q9Y5E5

ONC : See PCDHA1 for details PCDHB5 Protocadherin beta 5 ? PHY : See PCDHA1 for details [1] http://www.uniprot.org/uniprot/Q9Y5E4

ONC : See PCDHA1 for details PCDHB6 Protocadherin beta 6 ? PHY : See PCDHA1 for details [1] http://www.uniprot.org/uniprot/Q9Y5E3

ONC : See PCDHA1 for details PCDHB7 Protocadherin beta 7 ? PHY : See PCDHA1 for details [1] http://www.uniprot.org/uniprot/Q9Y5E2

ONC : See PCDHA1 for details PCDHB8 Protocadherin beta 8, PCDH3I ? PHY : See PCDHA1 for details [1] http://www.uniprot.org/uniprot/Q9UN66

ONC : See PCDHA1 for details PCDHB9 Protocadherin beta 9, PCDH3H ? PHY : See PCDHA1 for details [1] http://www.uniprot.org/uniprot/Q9Y5E1

ONC : See PCDHA1 for details PCDHB10 Protocadherin beta 10 ? PHY : See PCDHA1 for details [1] http://www.uniprot.org/uniprot/Q9UN67

ONC : See PCDHA1 for details PCDHB11 Protocadherin beta 11, Cadherin ME2 ? PHY : See PCDHA1 for details [1] http://www.uniprot.org/uniprot/Q9Y5F2

ONC : See PCDHA1 for details PCDHB12 Protocadherin beta 12 ? PHY : See PCDHA1 for details [1] http://www.uniprot.org/uniprot/Q9Y5F1

ONC : See PCDHA1 for details PCDHB13 Protocadherin beta 13 ? PHY : See PCDHA1 for details [1] http://www.uniprot.org/uniprot/Q9Y5F0

ONC : See PCDHA1 for details

MMMP Biomap #87 Page 56 PCDHB14 Protocadherin beta 14 ? PHY : See PCDHA1 for details [1] http://www.uniprot.org/uniprot/Q9Y5E9

ONC : See PCDHA1 for details PCDHB15 Protocadherin beta 15 ? PHY : See PCDHA1 for details [1] http://www.uniprot.org/uniprot/Q9Y5E8

ONC : See PCDHA1 for details PCDHB16 Protocadherin beta 16, Cadherin ME1 ? PHY : See PCDHA1 for details [1] http://www.uniprot.org/uniprot/Q9NRJ7

ONC : See PCDHA1 for details PCDHGA1 Protocadherin gamma subfamily A 1 ? PHY : See PCDHA1 for details [1] http://www.uniprot.org/uniprot/Q9Y5H4

ONC : See PCDHA1 for details PCDHGA2 Protocadherin gamma subfamily A 2 ? PHY : See PCDHA1 for details [1] http://www.uniprot.org/uniprot/Q9Y5H1

ONC : See PCDHA1 for details PCDHGA3 Protocadherin gamma subfamily A 3 ? PHY : See PCDHA1 for details [1] http://www.uniprot.org/uniprot/Q9Y5H0

ONC : See PCDHA1 for details PCDHGA4 Protocadherin gamma subfamily A 4 ? PHY : See PCDHA1 for details [1] http://www.uniprot.org/uniprot/Q9Y5G9

ONC : See PCDHA1 for details PCDHGA5 Protocadherin gamma subfamily A 5, ? PHY : See PCDHA1 for details [1] http://www.uniprot.org/uniprot/Q9Y5G8 Cadherin ME3 ONC : See PCDHA1 for details PCDHGA6 Protocadherin gamma subfamily A 6 ? PHY : See PCDHA1 for details [1] http://www.uniprot.org/uniprot/Q9Y5G7

ONC : See PCDHA1 for details PCDHGA7 Protocadherin gamma subfamily A 7 ? PHY : See PCDHA1 for details [1] http://www.uniprot.org/uniprot/Q9Y5G6

ONC : See PCDHA1 for details PCDHGA8 Protocadherin gamma subfamily A 8 ? PHY : See PCDHA1 for details [1] http://www.uniprot.org/uniprot/Q9Y5G5

ONC : See PCDHA1 for details PCDHGA9 Protocadherin gamma subfamily A 9 ? PHY : See PCDHA1 for details [1] http://www.uniprot.org/uniprot/Q9Y5G4

ONC : See PCDHA1 for details

MMMP Biomap #87 Page 57 PCDHGA10 Protocadherin gamma subfamily A 11 ? PHY : See PCDHA1 for details [1] http://www.uniprot.org/uniprot/Q9Y5H3

ONC : See PCDHA1 for details PCDHGA11 Protocadherin gamma subfamily A 11 ? PHY : See PCDHA1 for details [1] Waha A, Neoplasia 2005, 7:193-9

ONC : Epigenetic silencing of the protocadherin family member PCDH-gamma- A11 in astrocytomas [1]. See PCDHA1 for more details PCDHGA12 Protocadherin gamma subfamily A 12, ? PHY : See PCDHA1 for details [1] Lu Y, PLoS Med 2006, 3:e467 CDH21 ONC : Belongs to a gene expression signature that predicts survival of patients with non- small cell lung cancer (NSCLC) [1]. See PCDHA1 for more details PECAM1 Platelet and endothelial cell adhesion PECAM1 (mainly), PHY : Expressed by endothelial cells (mainly [1] Woodfin A, Arterioscler Thromb Vasc Biol molecule, CD31, PECAM-1 integrin aVb3, CD38, at intercellular junctions); expressed to 2007, 27:2514-23. [2] Nico B, Histol Histopathol CD177 different degrees on leukocytes and platelets. 2008, 23:601-7. [3] Wobser M, Arch Dermatol Besides adhesive properties, PECAM1 Res 2006, 297:352-7. [4] Massi D, Virchows Arch 2002, 440:22-8 mediates cell signaling in inflammation, angiogenesis, platelet function, thrombosis and leukocyte migration through venular walls [1]. Binds tyrosine-phosphorylated b-catenin and modulates b-catenin localization. Potent suppressor of Bax-mediated apoptosis

ONC : Used to measure tumor microvascular density (MVD), which correlates with prognosis [2] (although in melanoma conflicting results are reported [3]). Plakoglobin JUP (junctional plakoglobin), DP3 Desmoglein, PHY : Desmosome formation (see the above [1] http://www.uniprot.org/uniprot/P14923. [2] (desmoplakin 3), DPIII, PDGB, PKGB, desmocollin Figure, in the Desmocollin box). Acts as a Kanazawa Y, Anticancer Res 2008, 28(2A):655- CTNNG (catenin gamma) homodimer. Interacts with MUC1. Belongs to 64. [3] Shafiei F, Oncogene 2008, 27:2602-12. the beta-catenin family. The presence of [4] Rieger-Christ KM, Br J Cancer 2005, 92:2153-9. [5] Williams BO, Oncogene 2000, plakoglobin in both desmosomes and 19:5720-8 intermediate junctions suggests it plays a central role in submembranous plaques. Defects in JUP are the cause of Naxos disease (NXD) - an autosomal recessive disorder combining diffuse non-epidermolytic palmoplantar keratoderma with

MMMP Biomap #87 Page 58 arrhythmogenic right ventricular dysplasia - and the cause of familial arrhythmogenic right ventricular dysplasia type 12 (ARVD12) [1]

ONC : Down-regulation of plakoglobin in soft tissue sarcoma is associated with a higher risk of pulmonary metastasis [2]. Autocrine growth hormone (GH)-stimulated increases in DNMT3A and DNMT3B expression mediate repression of plakoglobin gene transcription by direct hypermethylation of its promoter and consequent oncogenic effects in mammary carcinoma cells [3]. Restoration of plakoglobin expression in bladder carcinoma cell lines suppresses cell migration and tumorigenic potential [4]. Beta-catenin and its close homologue plakoglobin (gamma-catenin) are major constituents of submembranal cell-cell adhesion sites; in addition, beta-catenin is a key component in the canonical WNT pathway. Aberrantly activated beta-catenin signaling contributes to cancer progression by inducing [in complex with lymphocyte enhancer factor (LEF)/T-cell factor (TCF)] the transcription of proliferation-related genes such as D1 and c-Myc. Plakoglobin can also activate LEF/TCF-mediated transcription [5] PUNC Putative neuronal cell adhesion molecule - PHY : ? [1] Bergamaschi A, J Pathol 2008, 214:357-67

ONC : Along with MARCO and SPARC, appears to correlate with prognosis of breast cancer patients [1] SDK1 Sidekick homolog 1 (cell adhesion - PHY : Cell adhesion protein that guides axonal [1] Yamagata M, Cell 2002, 110: 649-60 molecule) terminals to specific synapses in developing neurons - ONC : - Selectin-E Selectin (endothelial), E-selectin, SELE, SELPLG PHY : Key role in immunoadhesion. Mediates [1] Tremblay PL, Cancer Res 2008, 68:5167-76. ESEL, ELAM (endothelial leukocyte CD44 [2] in the adhesion of blood neutrophils in [2] Zen K, PLoS ONE 2008, 3:e1826. [3] adhesion molecule), CD62E cytokine-activated endothelium through Hakomori S, Proc Natl Acad Sci USA 2002, interaction with SELPLG. Involved in 99:10231-3. [4] Fukuda MN, Cancer Res 2000, MMMP Biomap #87 Page 59 atherosclerosis 60:450-6. [5] Weishaupt C, Clin Cancer Res 2007, 13:2549-56 ONC : Promotes diapedesis, the passage of circulating tumor cells (CTC) across the endothelium (a critical determinant of metastasis formation) [1,2]. The carbohydrate determinant sialyl Lewis(a) is known to be expressed strongly on cancers of the digestive organs (this carbohydrate antigen, known as CA19-9, is the most frequently applied serum tumor marker for diagnosis of cancers in the digestive organs) and to serve as a ligand for vascular E-selectin in hematogenous metastasis of cancers [3]. A peptide mimic of E-selectin ligand inhibits sialyl Lewis X- dependent lung colonization of murine melanoma cells [4]. Low expression of selectin-E in melanoma specimens might underlie insufficient recruitment of cytotoxic T lymphocytes and thus limit the effectiveness of immunotherapy regimens [5] Selectin-L Selectin (leukocyte), L-selectin, SELL, SELPLG PHY : Mediates the adherence of lymphocytes [1] Hanley WD, FASEB J 2006, 20:337-9. [2] LSEL, LAM1, Leu-8, Lyam-1, PLNHR, CD44 [1] to endothelial cells of high endothelial venules Barthel SR, Expert Opin Ther Targets 2007, CD62L, LNHR (lymph node homing CD34 in peripheral lymph nodes. Key role in 11:1473-91. [3] Chen S, Methods Enzymol receptor) leukocyte migration during inflammation [2] 2006, 416:371-80

ONC : L-selectin, along with E- or P-selectin, mediates cell tethering and rolling interactions through the recognition of sialo-fucosylated Lewis carbohydrates expressed on structurally diverse protein-lipid ligands on circulating leukocytes or tumor cells [2] (including melanoma [3]) Selectin-P Selectin (platelet), PSEL (P-selectin), SELPLG PHY : Calcium-dependent receptor for myeloid [1] Thomas SN, J Biol Chem 2008, 283:15647- PADGEM, GMP140 (granule membrane CD44 [1] cells that binds to carbohydrates on 55. [2] Borsig L, Expert Rev Anticancer Ther protein 140), CD62P, LECAM3 neutrophils and monocytes. Mediates the 2008, 8:1247-55. [3] Hostettler N, FASEB J (leukocyte & endothelial cell adhesion interaction of activated endothelial cells or 2007, 21:3562-72. [4] Lee DY, Clin Cancer Res 2008, 14:2841-9. [5] Weishaupt C, Clin Cancer molecule 3) platelets with leukocytes Res 2007, 13:2549-56

ONC : During cancer metastasis the formation of platelet-tumor cell aggregates in the circulation facilitates immune evasion and the

MMMP Biomap #87 Page 60 microvascular arrest of tumor cells at distant sites: adhesion molecules such as integrins and P-selectin are involved in these platelet- tumor cell interactions [2]. Selectin-specific heparin derivatives inhibit metastasis formation in mouse melanoma models [3,4]. Low expression of selectin-E in melanoma specimens might underlie insufficient recruitment of cytotoxic T lymphocytes and thus limit the effectiveness of immunotherapy regimens [5] SELPLG Selectin-P ligand, CD162, PSGL-1 (P- Selectin-E PHY : A SLe(x)-type glycan that mediates [1] Veldman GM, J Biol Chem 1995, 270:16470- selectin glycoprotein 1) Selectin-L recruitment and rolling of leukocytes over 5 Selectin-P vascular surfaces during the initial steps of inflammation through calcium-dependent interaction with selectins (through their lectin/EGF domains). These interactions require sialyl Lewis X glycan modification of SELPLG

ONC : - SIGLEC1 Sialic acid-binding Ig-like lectin 1, Sialic acid-containing PHY : Macrophage-restricted adhesion [1] http://www.uniprot.org/uniprot/Q9BZZ2 CD169, sialoadhesin molecules molecule that mediates sialic-acid dependent binding to lymphocytes, granulocytes, monocytes, NK cells, B-cells and CD8+ T- cells [1]

ONC : - SIGLEC5 Sialic acid-binding Ig-like lectin 5, Sialic acid-containing PHY : Putative adhesion molecule that [1] http://www.uniprot.org/uniprot/O15389 CD170, OBBP2 (obesity-binding protein molecules mediates sialic-acid dependent binding to 2), CD33L2 (CD33 like 2) cells. Expressed by monocytic/myeloid lineage cells [1]

ONC : - SIGLEC6 Sialic acid-binding Ig-like lectin 6, Sialic acid-containing PHY : Putative adhesion molecule that [1] http://www.uniprot.org/uniprot/O43699 CD327, OBBP1 (obesity-binding protein molecules mediates sialic-acid dependent binding to 1), CD33L1 (CD33 like 1) cells. Expressed at high levels in placenta (cyto- and syncytiotrophoblastic cells) and at lower levels in spleen, peripheral blood leukocytes (predominantly B-cells) and small

MMMP Biomap #87 Page 61 intestine [1]

ONC : - SIGLEC7 Sialic acid-binding Ig-like lectin 7, Sialic acid-containing PHY : Putative adhesion molecule that [1] http://www.uniprot.org/uniprot/Q9Y286. [2] CD328, AIRM1 (adhesion inhibitory molecules mediates sialic-acid dependent binding to Mingari MC, Immunol Rev 2001, 181:260-8. [3] receptor molecule 1) cells. Contains a cytoplasmic immunoreceptor Miyazaki K, Cancer Res 2004, 64:4498-505 tyrosine-based inhibitor motif (ITIM): if phosphorylated this motif can bind the SH2 domain of phosphatases. In the immune response, CD328 acts as an inhibitory receptor upon ligand induced tyrosine phosphorylation by recruiting cytoplasmic phosphatases that block signal transduction through dephosphorylation of signaling molecules. Mediates inhibition of natural killer cells cytotoxicity [1]

ONC : Like CD33, SIGLEC7 blocks proliferation of normal and leukemic myeloid cells [2]. Loss of disialyl Lewis(a), the ligand for Siglec-7, is associated with increased sialyl Lewis (a) (the commonly used CA19.9 serum marker) expression on human colon cancer [3] SIGLEC8 Sialic acid-binding Ig-like lectin 8, SAF2 Sialic acid-containing PHY : Putative adhesion molecule that [1] http://www.uniprot.org/uniprot/Q9NYZ4 (sialoadhesin family member 2) molecules mediates sialic-acid dependent binding to cells. Contains a cytoplasmic immunoreceptor tyrosine-based inhibitor motif (ITIM) (see SIGLEC7) [1]

ONC : - SIGLEC9 Sialic acid-binding Ig-like lectin 9, CD329 Sialic acid-containing PHY : Putative adhesion molecule that [1] http://www.uniprot.org/uniprot/Q9Y336. [2] molecules mediates sialic-acid dependent binding to cells Biedermann B, Leuk Res 2007, 31:211-20 [1]

ONC : CD33 (Siglec-3) is expressed on most acute myeloid leukemia (AML) cells and is currently being exploited as a therapeutic target: SIGLEC9, a CD33-related molecule, was the most highly expressed among , while it was absent from normal bone marrow myeloid progenitors [2]

MMMP Biomap #87 Page 62 SIGLEC10 Sialic acid-binding Ig-like lectin 10, SLG2 Sialic acid-containing PHY : Putative adhesion molecule that [1] http://www.uniprot.org/uniprot/Q96LC7 molecules mediates sialic-acid dependent binding to cells. In the immune response, may act as an inhibitory receptor upon ligand induced tyrosine phosphorylation by recruiting cytoplasmic phosphatase(s) via their SH2 domain(s) that block signal transduction through dephosphorylation of signaling molecules. Expressed by peripheral blood leukocytes (eosinophils, monocytes and a natural killer cell subpopulation) [1]

ONC : - SIGLEC11 Sialic acid-binding Ig-like lectin 11 Sialic acid-containing PHY : Putative adhesion molecule that [1] http://www.uniprot.org/uniprot/Q96RL6 molecules mediates sialic-acid dependent binding to cells. Contains 1 copy of a cytoplasmic motif that is referred to as the immunoreceptor tyrosine-based inhibitor motif (ITIM). This motif is involved in modulation of cellular responses. The phosphorylated ITIM motif can bind the SH2 domain of several SH2-containing phosphatases [1]

ONC : - SIGLEC12 Sialic acid-binding Ig-like lectin 12, Sialic acid-containing PHY : Putative adhesion molecule that [1] http://www.uniprot.org/uniprot/Q96PQ1 SIGLECL1 molecules mediates sialic-acid dependent binding to cells. The short isoform is highly expressed in spleen, small intestine and adrenal gland; it is lower expressed in thyroid, placenta, brain, stomach, bone marrow, spinal chord and beast. The long isoform is highly expressed in spleen, small intestine and bone marrow; it is lower expressed in thyroid, placenta, thymus, trachea, stomach, lung, adrenal gland, fetal brain and testis. Contains 1 copy of a cytoplasmic motif that is referred to as the immunoreceptor tyrosine-based inhibitor motif (ITIM). This motif is involved in modulation of cellular responses [1]

ONC : - SIGLEC14 Sialic acid-binding Ig-like lectin 14 Sialic acid-containing PHY : Putative adhesion molecule. Sialic acid- [1] http://www.uniprot.org/uniprot/Q08ET2 MMMP Biomap #87 Page 63 molecules binding paired receptor which may activate associated receptors. Interacts with TYROBP. Mainly expressed in hematopoietic tissues including bone marrow, spleen and fetal liver [1]

ONC : - SIGLEC15 Sialic acid-binding Ig-like lectin 15, Sialic acid-containing PHY : Binds sialylated glycoproteins. Interacts [1] http://www.uniprot.org/uniprot/Q6ZMC9 CD33L3 (CD33 like 3) molecules with TYROBP and HCST. Expressed in macrophage and/or dendritic cells of spleen and lymph nodes [1]

ONC : - Syndecan 1 SDC1, SYND1, CD138 Miscellany PHY : Cell surface proteoglycan that bears [1] Bartlett AH, Mol Cells 2007, 24:153-66. [2] both and chondroitin sulfate Morgan MR, Nat Rev Mol Cell Biol 2007, 8:957- and that links the cytoskeleton to the 69. [3] Fears CY, Matrix Biol 2006, 25:443-56. interstitial matrix. Anchorage of cells to [4] Su G, Cancer Res 2008, 68:9558-65. [5] Loussouarn D, Br J Cancer 2008, 98:1993-8. [6] "heparin"-binding domains that are prevalent Nikolova V, Carcinogenesis 2009, Epub ahead in extracellular matrix (ECM) components is of print thought to occur primarily through the syndecans. Syndecans interact with a wide variety of molecules, including growth factors, cytokines, proteinases, adhesion receptors and extracellular matrix components, through their heparan sulfate chains. Recent studies indicate that these interactions not only regulate key events in development and homeostasis, but also key mechanisms of the host inflammatory response and tissue injury repair [1,2]

ONC : In some cancers, syndecan expression has been shown to regulate tumor cell function (e.g. proliferation, adhesion, and motility) and serve as a prognostic marker for tumor progression and patient survival [3]. fibroblast-derived MT1-MMP cleaves Sdc1 at the fibroblast surface, leading to paracrine growth stimulation of breast carcinoma cells by Sdc1 ectodomain [4]. A significant correlation was found between the loss of syndecan-1 epithelial expression and the

MMMP Biomap #87 Page 64 syndecan-1 stromal expression with high grade of breast cancer [5]. Soluble- and membrane-bound forms of Syndecan-1 play different roles at different stages of breast cancer progression: proteolytic conversion of Syndecan-1 from a membrane-bound into a soluble molecule marks a switch from a proliferative to an invasive phenotype [6] Syndecan 2 SDC2, SYND2, HSPG1 (heparan sulfate Miscellany PHY : The syndecans comprise a family of cell [1] http://www.uniprot.org/uniprot/P34741. [2] proteoglycan 1), fibroglycan surface heparan sulfate Munesue S, J Biol Chem 2007, 282:28164-74. exhibiting complex biological functions [3] Orosco A, Cancer Res 2007, 67:3708-15. [4] involving the interaction of heparan sulfate Park H, Cancer Res 2005, 65:9899-905. [5] Kim Y, Oncogene 2003, 22:826-30 side chains with a variety of soluble and insoluble heparin-binding extracellular ligands [1]

ONC : Syndecan-2 acts as a suppressor for matrix metalloproteinase-2 (MMP-2) activation, causing suppression of metastasis in the Lewis lung carcinoma 3LL metastatic system [2]. Plus, overexpression of syndecan- 2 sensitized human osteosarcoma cells to chemotherapy-induced apoptosis [3]. However, data suggest that syndecan-2 regulates the tumorigenic activities of HT1080 fibrosarcoma cells and that FAK is a key regulator of syndecan-2-mediated tumorigenic activities [4]; plus reduced syndecan-2 expression correlates with reduced tumorigenic activity in colon carcinoma cells [5] Syndecan 3 SDC3, SYND3, N-syndecan Miscellany PHY : May have a role in the organization of [1] http://www.uniprot.org/uniprot/O75056 cell shape by affecting the actin cytoskeleton, possibly by transferring signals from the cell surface in a sugar-dependent mechanism. Expressed in the nervous system, the adrenal gland, and the spleen [1]

ONC : - Syndecan 4 SDC4, SYND4, amphiglycan, ryudocan Syntenin PHY : Belongs to the syndecan proteoglycan [1] http://www.uniprot.org/uniprot/P31431. [2] family along with SDC1, SDC2 and SDC3. Baba F, Breast Cancer Res Treat 2006, 98:91- Expressed in epithelial and fibroblastic cells 8. [3] Chalkiadaki G, Int J Biochem Cell Biol

MMMP Biomap #87 Page 65 [1] 2008, Epub ahead of print

ONC : Syndecan-1 and syndecan-4 are overexpressed in an estrogen receptor- negative, highly proliferative breast carcinoma subtype [2]. Fibroblast growth factor-2 (FGF- 2), the most abundant growth factor produced by melanoma cells but not by normal melanocytes, specifically regulates melanoma cell ability to migrate through a syndecan-4- dependent mechanism [3] TJP1 , ZO-1 (zona TJP1 PHY : Tight junction (TJ) formation. Acts as a [1] Hoover KB, Am J Pathol 1998, 153:1767-73. occludens 1) TJP2 homodimer or heterodimer with TJP2 and [2] Kleeff J, Pancreas 2001, 23:259-65. [3] TJP3 TJP3. Interacts with occludin, claudins, Kaihara T, J Exp Clin Cancer Res 2003, 22:117- CGN/cingulin 23. [4] Polette M, Cells Tissues Organs 2007, 185:61-5. [5] Fiorini C, Biochim Biophys Acta 2008, 1778:56-67 ONC : Reduced expression in breast cancer [1], increased in pancreatic cancer [2]. Decreased expression of adhesion molecules, E-cadherin and ZO-1, in colorectal cancer are closely related to liver metastasis [3]. Cytoplasmic/nuclear relocalization of beta- catenin and ZO-1 from the adherens and tight junctions are common processes of the epithelial-mesenchymal transition (EMT) associated with tumor invasion [4]. Accelerated internalization of junctional membrane proteins (connexin 43, N-cadherin and ZO-1) within endocytic vacuoles is an early event in carcinogenesis induced by DDT (a non-genomic carcinogen) [5] TJP2 , ZO-2 (zona TJP1 PHY : Tight junction (TJ) formation. [1] Glaunsinger BA, EMBO J 2001, 20:5578-86. occludens 2) TJP2 Homodimer and heterodimer with ZO1. [2] Fink C, Neoplasia 2006, 8:1019-27 Interacts with occludin. Defects in TJP2 are involved in familial hypercholanemia (FHCA), a disorder characterized by elevated serum concentrations, itching and fat malabsorption

ONC : Adenoviral protein Ad9 E4-ORF1 exerts its oncogenic potential at least in part by complexing with candidate tumor suppressor

MMMP Biomap #87 Page 66 protein ZO-2 [1]. Expression of ZO-1 and ZO- 2 is reduced (with loss of blood-testis barrier integrity) in testicular carcinoma in situ [2] TJP3 Tight junction protein 3, ZO-3 (zona TJP1 PHY : Tight junction (TJ) formation. Interacts [1] http://www.uniprot.org/uniprot/O95049 occludens 3) with occludin, claudins and ZO-1

ONC : -

VCAM1 Vascular cell adhesion molecule 1, ITG alpha4-beta1 PHY : Regulates leukocyte migration from the [1] Haverslag R, Cardiovasc Hematol Disord CD106 blood into tissues during inflammation; Drug Targets 2008, 8:252-60. [2] Curr Med expressed on inflamed vascular endothelium, Chem 2007, 14:377-86. [3] Liang S, Am J as well as on macrophage-like and dendritic Physiol Cell Physiol 2008, 295:C701-7. [4] cell types in both normal and inflamed tissue. VCAM-1 expression is stimulated by Klemke M, J Cell Physiol 2007, 212:368-74. [5] inflammatory cytokines (e.g. IL-1, TNF) [1] Wu TC, Cancer Res 2007, 67:6003-6

ONC : Like other cell adhesion molecules, mediates malignant cell extravasation and thus metastasis formation in different tumor models [2], including melanoma [3,4]. Tumor overexpressing VCAM1 may escape immune surveillance [5].

Name Aliases Binding partner Physiology / Oncology References

MMMP Biomap #87 Page 67