DOCSLIB.ORG

Eph Receptors and Ephrins in Cancer: Bidirectional Signalling and Beyond

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Eph Receptors and Ephrins in Cancer: Bidirectional Signalling and Beyond REVIEWS Eph receptors and ephrins in cancer: bidirectional signalling and beyond Elena B. Pasquale Abstract | The Eph receptor tyrosine kinases and their ephrin ligands have intriguing expression patterns in cancer cells and tumour blood vessels, which suggest important roles for their bidirectional signals in many aspects of cancer development and progression. Eph gene mutations probably also contribute to cancer pathogenesis. Eph receptors and ephrins have been shown to affect the growth, migration and invasion of cancer cells in culture as well as tumour growth, invasiveness, angiogenesis and metastasis in vivo. However, Eph signalling activities in cancer seem to be complex, and are characterized by puzzling dichotomies. Nevertheless, the Eph receptors are promising new therapeutic targets in cancer. Eph receptors and their Eph receptor-interacting (ephrin) Eph and ephrin families ligands together form an important cell communication In the human genome there are nine EphA receptors, system with widespread roles in normal physiology and which promiscuously bind five glycosylphosphatidyl- disease pathogenesis1. Links between Eph receptors inositol (GPI)-linked ephrin-A ligands, and five EphB and cancer date back to the first identified Eph family receptors, which promiscuously bind three transmem- member2. EPHA1 was cloned from a carcinoma cell brane ephrin-B ligands5. Exceptions are the EPHA4 line in a screen for new oncogenic tyrosine kinases. This and EPHB2 receptors, which can also bind ephrin-Bs and novel receptor was found to be upregulated in tumour ephrin‑A5, respectively, and EPHB4, which prefer- tissues compared with normal tissues and its overexpres- entially binds ephrin‑B2 only. Eph receptors typically sion caused the oncogenic transformation of NIH3T3 interact with the cell surface-associated ephrins at sites fibroblasts2,3. The first ephrin ligand, ephrin-A1, was of cell–cell contact (FIG. 1). In addition, soluble ephrin-As also identified from cancer cells a few years later4. The released from the cell surface retain the ability to activate evidence implicating Eph receptors and ephrins in EPHA2 (REFS 4,9,10). cancer is now extensive and continues to grow. Eph–ephrin complexes emanate bidirectional sig- The activities of the Eph system in cancer are com- nals: forward signals that depend on Eph kinase activity plex, and intriguing in their paradoxical effects. For propagate in the receptor-expressing cell, and reverse example, multiple Eph receptors and/or ephrins are signals that depend on Src family kinases propagate present in most cancer cells. However, both increased in the ephrin-expressing cell. Ephrin-dependent but and decreased Eph expression has been linked to can- kinase-independent Eph signals can also occur11–13. Eph cer progression. Consistent with this dichotomy, there signalling controls cell morphology, adhesion, migration is good evidence that Eph receptors and ephrins can and invasion by modifying the organization of the actin both promote and inhibit tumorigenicity. The factors cytoskeleton and influencing the activities of integrins responsible for these divergent activities are only now and intercellular adhesion molecules1,5. Recent work beginning to be uncovered. has also uncovered Eph effects on cell proliferation and Following a brief overview of the Eph and ephrin survival as well as specialized cellular functions such as Sanford-Burnham Medical Research Institute, families and their bidirectional signalling mecha- synaptic plasticity, insulin secretion, bone remodelling 1 10901 N. Torrey Pines Rd., nisms, the factors that regulate their expression and and immune function . La Jolla, CA 92037, USA, the remarkable multiplicity of their roles in cancer Bidirectional signals can lead to the removal of the and Pathology Department, are discussed, and the strategies under evaluation to adhesive Eph–ephrin complexes from cell contact sites University of California target the Eph system for cancer therapy outlined. through an unusual endocytic mechanism that involves San Diego, La Jolla, CA 92093, USA. Other reviews provide more in-depth information on their internalization, together with patches of the sur- e-mail: [email protected] Eph signalling mechanisms in development and adult rounding plasma membranes, into the receptor- or doi:10.1038/nrc2806 physiology1,5–8. ephrin-expressing cell5. This enables the separation of NATURE REVIEWS | CANCER VOLUME 10 | MARCH 2010 | 165 © 2010 Macmillan Publishers Limited. All rights reserved REVIEWS At a glance Eph receptor and ephrin expression controls many processes that are crucial for development and tissue • The Eph receptors are the largest family of receptor tyrosine kinases. They bind homeostasis, including the formation of tissue bounda- glycosylphosphatidylinositol (GPI)-linked and transmembrane ephrin ligands, ries, assembly of intricate neuronal circuits, remodelling generating bidirectional signals at sites of cell–cell contact. of blood vessels and organ size1,5. Many Eph receptors • Eph receptors and/or ephrins are widely expressed in cancer cells and tumour and/or ephrins are also expressed in both cancer cells and stroma, but they can be downregulated at advanced cancer stages. Often Eph the tumour microenvironment, where they influence receptor and ephrin levels are discordantly regulated. In addition to changes in expression levels, Eph receptor mutations are also likely to have a role in cancer tumour properties by enabling aberrant cell–cell com- 26–32 pathogenesis. munication in and between tumour compartments . Mutations dysregulating Eph function are also likely to • In many cellular contexts, Eph bidirectional signalling promotes an epithelial phenotype and suppresses cancer cell–substrate adhesion, migration, invasion and have a role in cancer progression. growth. Consistent with this, Eph receptor signalling seems to be low in many cancer cells owing to an imbalance of Eph and ephrin expression or the inability of receptor Expression in cancer cells. Many studies have correlated and ligand to interact effectively. Eph and ephrin expression levels with cancer progres- • Eph receptors and ephrins can also promote cancer progression through poorly sion, metastatic spread and patient survival (TABLE 1). understood mechanisms that do not involve reciprocal association but rather depend EPHA2, for example, is upregulated in many cancers on crosstalk with oncogenic signalling pathways. In addition, Eph bidirectional and its expression has been linked to increased malig- signals promote tumour angiogenesis. nancy and a poor clinical prognosis27,28,31,33. Furthermore, • Eph receptors and ephrins are promising new therapeutic targets in cancer, and many EPHA2 seems to be preferentially expressed in malignant Eph-based approaches show promise for prognosis and therapy. breast and prostate cancers with a basal phenotype34,35. EPHB4 is also widely expressed in cancer cells and its increased abundance has been correlated with cancer the engaged cell surfaces to produce the characteristic progression29,36,37. However, decreased Eph or ephrin Eph-repulsive responses. Another mechanism allow- levels in malignant cancer cell lines and tumour speci- ing cell separation involves protease-mediated cleav- mens have also been reported. For example, EPHA1 age of the Eph or ephrin extracellular domains14–18. is downregulated in advanced human skin and Internalization and cleavage result in degradation, which colorectal cancers38,39, EphB receptors in advanced color- can profoundly downregulate Eph levels. However, in ectal cancer23,40–42 and ephrin-A5 in glioblastomas43. certain cellular contexts Eph–ephrin complexes persist Furthermore, EPHB6 expression is lower in metastatic at intercellular junctions and emanate prolonged bidirec- than non-metastatic lung cancers44. Reconciling these tional signals that favour adhesiveness. For example, the discrepancies, recent studies show that an initial Eph cell adhesion molecule E-cadherin promotes EPHA2– receptor upregulation (that is due to activated oncogenic ephrin-A1 localization at epithelial cell junctions and the signalling pathways and other factors) can be followed metalloprotease ADAM19 stabilizes EPHA4–ephrin-A5 by epigenetic silencing in more advanced stages owing at neuromuscular junctions independently of its pro- to promoter hypermethylation, as shown for several teolytic activity19–21. A combination of Eph-dependent EphB receptors and EPHA1 in colorectal cancer23,39–41. repulsive and adhesive forces can drive the segregation Transcriptional repression, such as repression of EPHB2 of cell populations expressing different combinations of by REL (a member of the nuclear factor-κB family) in Eph receptors and ephrins, which may include trans- colorectal cancer, may also play a part in Eph silencing45. formed and normal cells or divergent subpopulations of Intriguingly, differential transcriptional regulation has tumour cells5,22,23. been reported for EPHB2 and EPHB4 during colorectal There is also increasing evidence that other signal- cancer progression37. This was attributed to a switch in Basal phenotype ling modalities beyond ‘conventional’ bidirectional sig- the association of β-catenin from the p300 co-activator Highly aggressive breast and nalling contribute to the multiple activities of the Eph (which induces EPHB2 transcription) to the CREB bind- prostate cancers with gene expression profiles similar to system in cancer. For example, an initial extracellular ing protein (CBP)
Load more

Recommended publications
  • Ephrin-A4/Fc Chimera Human
    EPHRIN-A4 EXTRACELLULAR DOMAIN/FC CHIMERA Human, Recombinant Expressed in NSO mouse myeloma cells Product Number E 0403 Storage Temperature –20 °C Synonyms: LERK-4; EFL-4 Reagents Recombinant human Ephrin-A4 extracellular domain/Fc Product Description chimera is supplied as approximately 200 mg of protein Recombinant human Ephrin-A4 extracellular domain/Fc lyophilized from a sterile-filtered phosphate-buffered chimera consists of amino acid residues 1-171 saline (PBS) solution. 1 (extracellular domain of human Ephrin-A4) that was fused by means of a polypeptide linker to the Fc portion Preparation Instructions of human IgG1 that is 6X histidine-tagged at the Reconstitute the vial contents with sterile PBS. carboxyl terminus. The chimeric protein is expressed in Stock solution concentration should be no less than a mouse myeloma cell line, NSO. Recombinant Ephrin 100 µg/ml. A4 is a disulfide-linked homodimer. The amino terminus is Leu 26 determined by N-terminal Storage/Stability sequencing. The calculated molecular mass of the Lyophilized samples are stable for greater than six reduced protein is approximately 43.7 kDa, but as a months at –20 °C. Upon reconstitution, store at 2-4 °C result of glycosylation, the recombinant Ephrin-A4/Fc for up to one month. For extended storage, store in migrates as an approximately 50 kDa protein on working aliquots at –20 °C. Repeated freeze-thaw reducing SDS -PAGE. cycles should be avoided. Do not store in frost-free freezer. The Ephrin ligand family, of which Ephrin-A4 is a member, binds members of the Eph receptor family. All Product Profile ligands share a conserved extracellular sequence, Identity of Ephrin-A4/Fc was determined by western thought to correspond to the receptor binding domain.
    [Show full text]
  • Epha Receptors and Ephrin-A Ligands Are Upregulated by Monocytic
    Mukai et al. BMC Cell Biology (2017) 18:28 DOI 10.1186/s12860-017-0144-x RESEARCHARTICLE Open Access EphA receptors and ephrin-A ligands are upregulated by monocytic differentiation/ maturation and promote cell adhesion and protrusion formation in HL60 monocytes Midori Mukai, Norihiko Suruga, Noritaka Saeki and Kazushige Ogawa* Abstract Background: Eph signaling is known to induce contrasting cell behaviors such as promoting and inhibiting cell adhesion/ spreading by altering F-actin organization and influencing integrin activities. We have previously demonstrated that EphA2 stimulation by ephrin-A1 promotes cell adhesion through interaction with integrins and integrin ligands in two monocyte/ macrophage cell lines. Although mature mononuclear leukocytes express several members of the EphA/ephrin-A subclass, their expression has not been examined in monocytes undergoing during differentiation and maturation. Results: Using RT-PCR, we have shown that EphA2, ephrin-A1, and ephrin-A2 expression was upregulated in murine bone marrow mononuclear cells during monocyte maturation. Moreover, EphA2 and EphA4 expression was induced, and ephrin-A4 expression was upregulated, in a human promyelocytic leukemia cell line, HL60, along with monocyte differentiation toward the classical CD14++CD16− monocyte subset. Using RT-PCR and flow cytometry, we have also shown that expression levels of αL, αM, αX, and β2 integrin subunits were upregulated in HL60 cells along with monocyte differentiation while those of α4, α5, α6, and β1 subunits were unchanged. Using a cell attachment stripe assay, we have shown that stimulation by EphA as well as ephrin-A, likely promoted adhesion to an integrin ligand- coated surface in HL60 monocytes. Moreover, EphA and ephrin-A stimulation likely promoted the formation of protrusions in HL60 monocytes.
    [Show full text]
  • Neurotrophin-3 Production Promotes Human Neuroblastoma Cell Survival by Inhibiting Trkc-Induced Apoptosis
    Neurotrophin-3 production promotes human neuroblastoma cell survival by inhibiting TrkC-induced apoptosis Jimena Bouzas-Rodriguez, … , Servane Tauszig-Delamasure, Patrick Mehlen J Clin Invest. 2010;120(3):850-858. https://doi.org/10.1172/JCI41013. Research Article Oncology Tropomyosin-related kinase receptor C (TrkC) is a neurotrophin receptor with tyrosine kinase activity that was expected to be oncogenic. However, it has several characteristics of a tumor suppressor: its expression in tumors has often been associated with good prognosis; and it was recently demonstrated to be a dependence receptor, transducing different positive signals in the presence of ligand but inducing apoptosis in the absence of ligand. Here we show that the TrkC ligand neurotrophin-3 (NT-3) is upregulated in a large fraction of aggressive human neuroblastomas (NBs) and that it blocks TrkC-induced apoptosis of human NB cell lines, consistent with the idea that TrkC is a dependence receptor. Functionally, both siRNA knockdown of NT-3 expression and incubation with a TrkC-specific blocking antibody triggered apoptosis in human NB cell lines. Importantly, disruption of the NT-3 autocrine loop in malignant human neuroblasts triggered in vitro NB cell death and inhibited tumor growth and metastasis in both a chick and a mouse xenograft model. Thus, we believe that our data suggest that NT-3/TrkC disruption is a putative alternative targeted therapeutic strategy for the treatment of NB. Find the latest version: https://jci.me/41013/pdf Research article Neurotrophin-3 production promotes human neuroblastoma cell survival by inhibiting TrkC-induced apoptosis Jimena Bouzas-Rodriguez,1 Jorge Ruben Cabrera,1 Céline Delloye-Bourgeois,1 Gabriel Ichim,1 Jean-Guy Delcros,1 Marie-Anne Raquin,2 Raphaël Rousseau,3 Valérie Combaret,3 Jean Bénard,4 Servane Tauszig-Delamasure,1 and Patrick Mehlen1 1Apoptosis, Cancer and Development Laboratory–Equipe labellisée “La Ligue,” CNRS UMR5238, Université de Lyon, France.
    [Show full text]
  • Ephrin-A1 Expression Contributes to the Malignant Characteristics of A
    843 HEPATOBILIARY DISEASE Ephrin-A1 expression contributes to the malignant Gut: first published as 10.1136/gut.2004.049486 on 11 May 2005. Downloaded from characteristics of a-fetoprotein producing hepatocellular carcinoma H Iida, M Honda, H F Kawai, T Yamashita, Y Shirota, B-C Wang, H Miao, S Kaneko ............................................................................................................................... Gut 2005;54:843–851. doi: 10.1136/gut.2004.049486 Background and aims: a-Fetoprotein (AFP), a tumour marker for hepatocellular carcinoma (HCC), is associated with poor prognosis. Using cDNA microarray analysis, we previously found that ephrin-A1, an angiogenic factor, is the most differentially overexpressed gene in AFP producing hepatoma cell lines. In the present study, we investigated the significance of ephrin-A1 expression in HCC. See end of article for Methods: We examined ephrin-A1 expression and its effect on cell proliferation and gene expression in authors’ affiliations five AFP producing hepatoma cell lines, three AFP negative hepatoma cell lines, and 20 human HCC ....................... specimens. Correspondence to: Results: Ephrin-A1 expression levels were lowest in normal liver tissue, elevated in cirrhotic tissue, and Dr S Kaneko, Department further elevated in HCC specimens. Ephrin-A1 expression was strongly correlated with AFP expression of Cancer Gene (r = 0.866). We showed that ephrin-A1 induced expression of AFP. This finding implicates ephrin-A1 in Regulation, Kanazawa University Graduate the mechanism of AFP induction in HCC. Ephrin-A1 promoted the proliferation of ephrin-A1 School of Medical Science, underexpressing HLE cells, and an ephrin-A1 antisense oligonucleotide inhibited the proliferation of 13-1 Takara-Machi, ephrin-A1 overexpressing Huh7 cells.
    [Show full text]
  • Engrailed and Fgf8 Act Synergistically to Maintain the Boundary Between Diencephalon and Mesencephalon Scholpp, S., Lohs, C
    5293 Erratum Engrailed and Fgf8 act synergistically to maintain the boundary between diencephalon and mesencephalon Scholpp, S., Lohs, C. and Brand, M. Development 130, 4881-4893. An error in this article was not corrected before going to press. Throughout the paper, efna4 should be read as EphA4, as the authors are referring to the gene encoding the ephrin A4 receptor (EphA4) and not to that encoding its ligand ephrin A4. We apologise to the authors and readers for this mistake. Research article 4881 Engrailed and Fgf8 act synergistically to maintain the boundary between diencephalon and mesencephalon Steffen Scholpp, Claudia Lohs and Michael Brand* Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG), Dresden, Germany Department of Genetics, University of Dresden (TU), Pfotenhauer Strasse 108, 01307 Dresden, Germany *Author for correspondence (e-mail: [email protected]) Accepted 23 June 2003 Development 130, 4881-4893 © 2003 The Company of Biologists Ltd doi:10.1242/dev.00683 Summary Specification of the forebrain, midbrain and hindbrain However, a patch of midbrain tissue remains between the primordia occurs during gastrulation in response to signals forebrain and the hindbrain primordia in such embryos. that pattern the gastrula embryo. Following establishment This suggests that an additional factor maintains midbrain of the primordia, each brain part is thought to develop cell fate. We find that Fgf8 is a candidate for this signal, as largely independently from the others under the influence it is both necessary and sufficient to repress pax6.1 and of local organizing centers like the midbrain-hindbrain hence to shift the DMB anteriorly independently of the boundary (MHB, or isthmic) organizer.
    [Show full text]
  • Supplemental Material 1
    Supplemental Fig. 1 12 1mg/ml A1AT p<0.001 10 8 p=0.004 6 p=0.029 (fold change) 4 mRNA ofmRNA angptl4 at h 1 2 0 Control Prolastin Aralast A1AT Sigma Supplemental Figure 1. Adherent PBMCs were incubated with 1 mg/ml A1AT from different sources (Prolastin, Grifols; Aralast, Baxter; or Sigma Aldrich) for 1h and mRNA levels of angplt4 were determined by RT-PCR. Bars represent the mean ± SD of four experiments. Supplemental Fig. 2 12 8 h p=0.005 10 8 6 mRNA angplt4 mRNA change Fold 4 2 0 Control A1AT 0.5 mg/ml Supplemental Figure 2. HMVEC-L were incubated with 0.5 mg/ml A1AT (Calbiochem) for 8 h and mRNA levels of angptl4 were determined by RT-PCR. Bars represent the mean ± SEM of three experiments. Supplemental Table I. Influence of A1AT (1 mg/ml, 8 h) on expression of angiogenesis genesa in HMVEC-L Unigene Symbol Description Gname fold changeb Hs.525622 AKT1 V-akt murine thymoma viral AKT/MGC99656/PKB/PKB- 0,94 0,14 oncogene homolog 1 ALPHA/PRKBA/RAC/RAC- ALPHA Hs.369675 ANGPT1 Angiopoietin 1 AGP1/AGPT/ANG1 3,61 5,11 Hs.583870 ANGPT2 Angiopoietin 2 AGPT2/ANG2 0,98 0,01 Hs.209153 ANGPTL3 Angiopoietin-like 3 ANGPT5/FHBL2 1,10 0,59 Hs.9613 ANGPTL4 Angiopoietin-like 4 ANGPTL2/ARP4/FIAF/HFAR 5,79 1,66 P/NL2/PGAR/pp1158 Hs.1239 ANPEP Alanyl (membrane) APN/CD13/GP150/LAP1/P150 1,03 0,01 aminopeptidase /PEPN Hs.194654 BAI1 Brain-specific angiogenesis FLJ41988/GDAIF 0,89 0,26 inhibitor 1 Hs.54460 CCL11 Chemokine (C-C motif) ligand 11 MGC22554/SCYA11 1,04 0,15 Hs.303649 CCL2 Chemokine (C-C motif) ligand 2 GDCF- 1,09 0,14 2/HC11/HSMCR30/MCAF/M CP-
    [Show full text]
  • On the Turning of Xenopus Retinal Axons Induced by Ephrin-A5
    Development 130, 1635-1643 1635 © 2003 The Company of Biologists Ltd doi:10.1242/dev.00386 On the turning of Xenopus retinal axons induced by ephrin-A5 Christine Weinl1, Uwe Drescher2,*, Susanne Lang1, Friedrich Bonhoeffer1 and Jürgen Löschinger1 1Max-Planck-Institute for Developmental Biology, Spemannstrasse 35, 72076 Tübingen, Germany 2MRC Centre for Developmental Neurobiology, King’s College London, New Hunt’s House, Guy’s Hospital Campus, London SE1 1UL, UK *Author for correspondence (e-mail: [email protected]) Accepted 13 January 2003 SUMMARY The Eph family of receptor tyrosine kinases and their turning or growth cone collapse when confronted with ligands, the ephrins, play important roles during ephrin-A5-Fc bound to beads. However, when added in development of the nervous system. Frequently they exert soluble form to the medium, ephrin-A5 induces growth their functions through a repellent mechanism, so that, for cone collapse, comparable to data from chick. example, an axon expressing an Eph receptor does not The analysis of growth cone behaviour in a gradient of invade a territory in which an ephrin is expressed. Eph soluble ephrin-A5 in the ‘turning assay’ revealed a receptor activation requires membrane-associated ligands. substratum-dependent reaction of Xenopus retinal axons. This feature discriminates ephrins from other molecules On fibronectin, we observed a repulsive response, with the sculpturing the nervous system such as netrins, slits and turning of growth cones away from higher concentrations class 3 semaphorins, which are secreted molecules. While of ephrin-A5. On laminin, retinal axons turned towards the ability of secreted molecules to guide axons, i.e.
    [Show full text]
  • Detection of Pro Angiogenic and Inflammatory Biomarkers in Patients With
    www.nature.com/scientificreports OPEN Detection of pro angiogenic and infammatory biomarkers in patients with CKD Diana Jalal1,2,3*, Bridget Sanford4, Brandon Renner5, Patrick Ten Eyck6, Jennifer Laskowski5, James Cooper5, Mingyao Sun1, Yousef Zakharia7, Douglas Spitz7,9, Ayotunde Dokun8, Massimo Attanasio1, Kenneth Jones10 & Joshua M. Thurman5 Cardiovascular disease (CVD) is the most common cause of death in patients with native and post-transplant chronic kidney disease (CKD). To identify new biomarkers of vascular injury and infammation, we analyzed the proteome of plasma and circulating extracellular vesicles (EVs) in native and post-transplant CKD patients utilizing an aptamer-based assay. Proteins of angiogenesis were signifcantly higher in native and post-transplant CKD patients versus healthy controls. Ingenuity pathway analysis (IPA) indicated Ephrin receptor signaling, serine biosynthesis, and transforming growth factor-β as the top pathways activated in both CKD groups. Pro-infammatory proteins were signifcantly higher only in the EVs of native CKD patients. IPA indicated acute phase response signaling, insulin-like growth factor-1, tumor necrosis factor-α, and interleukin-6 pathway activation. These data indicate that pathways of angiogenesis and infammation are activated in CKD patients’ plasma and EVs, respectively. The pathways common in both native and post-transplant CKD may signal similar mechanisms of CVD. Approximately one in 10 individuals has chronic kidney disease (CKD) rendering CKD one of the most common diseases worldwide1. CKD is associated with a high burden of morbidity in the form of end stage kidney disease (ESKD) requiring dialysis or transplantation 2. Furthermore, patients with CKD are at signifcantly increased risk of death from cardiovascular disease (CVD)3,4.
    [Show full text]
  • Type of the Paper (Article
    Table S1. Gene expression of pro-angiogenic factors in tumor lymph nodes of Ibtk+/+Eµ-myc and Ibtk+/-Eµ-myc mice. Fold p- Symbol Gene change value 0,007 Akt1 Thymoma viral proto-oncogene 1 1,8967 061 0,929 Ang Angiogenin, ribonuclease, RNase A family, 5 1,1159 481 0,000 Angpt1 Angiopoietin 1 4,3916 117 0,461 Angpt2 Angiopoietin 2 0,7478 625 0,258 Anpep Alanyl (membrane) aminopeptidase 1,1015 737 0,000 Bai1 Brain-specific angiogenesis inhibitor 1 4,0927 202 0,001 Ccl11 Chemokine (C-C motif) ligand 11 3,1381 149 0,000 Ccl2 Chemokine (C-C motif) ligand 2 2,8407 298 0,000 Cdh5 Cadherin 5 2,5849 744 0,000 Col18a1 Collagen, type XVIII, alpha 1 3,8568 388 0,003 Col4a3 Collagen, type IV, alpha 3 2,9031 327 0,000 Csf3 Colony stimulating factor 3 (granulocyte) 4,3332 258 0,693 Ctgf Connective tissue growth factor 1,0195 88 0,000 Cxcl1 Chemokine (C-X-C motif) ligand 1 2,67 21 0,067 Cxcl2 Chemokine (C-X-C motif) ligand 2 0,7507 631 0,000 Cxcl5 Chemokine (C-X-C motif) ligand 5 3,921 328 0,000 Edn1 Endothelin 1 3,9931 042 0,001 Efna1 Ephrin A1 1,6449 601 0,002 Efnb2 Ephrin B2 2,8858 042 0,000 Egf Epidermal growth factor 1,726 51 0,000 Eng Endoglin 0,2309 467 0,000 Epas1 Endothelial PAS domain protein 1 2,8421 764 0,000 Ephb4 Eph receptor B4 3,6334 035 V-erb-b2 erythroblastic leukemia viral oncogene homolog 2, 0,000 Erbb2 3,9377 neuro/glioblastoma derived oncogene homolog (avian) 024 0,000 F2 Coagulation factor II 3,8295 239 1 0,000 F3 Coagulation factor III 4,4195 293 0,002 Fgf1 Fibroblast growth factor 1 2,8198 748 0,000 Fgf2 Fibroblast growth factor
    [Show full text]
  • Functional Analysis of Somatic Mutations Affecting Receptor Tyrosine Kinase Family in Metastatic Colorectal Cancer
    Author Manuscript Published OnlineFirst on March 29, 2019; DOI: 10.1158/1535-7163.MCT-18-0582 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Functional analysis of somatic mutations affecting receptor tyrosine kinase family in metastatic colorectal cancer Leslie Duplaquet1, Martin Figeac2, Frédéric Leprêtre2, Charline Frandemiche3,4, Céline Villenet2, Shéhérazade Sebda2, Nasrin Sarafan-Vasseur5, Mélanie Bénozène1, Audrey Vinchent1, Gautier Goormachtigh1, Laurence Wicquart6, Nathalie Rousseau3, Ludivine Beaussire5, Stéphanie Truant7, Pierre Michel8, Jean-Christophe Sabourin9, Françoise Galateau-Sallé10, Marie-Christine Copin1,6, Gérard Zalcman11, Yvan De Launoit1, Véronique Fafeur1 and David Tulasne1 1 Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T – Mechanisms of Tumorigenesis and Target Therapies, F-59000 Lille, France. 2 Univ. Lille, Plateau de génomique fonctionnelle et structurale, CHU Lille, F-59000 Lille, France 3 TCBN - Tumorothèque Caen Basse-Normandie, F-14000 Caen, France. 4 Réseau Régional de Cancérologie – OncoBasseNormandie – F14000 Caen – France. 5 Normandie Univ, UNIROUEN, Inserm U1245, IRON group, Rouen University Hospital, Normandy Centre for Genomic and Personalized Medicine, F-76000 Rouen, France. 6 Tumorothèque du C2RC de Lille, F-59037 Lille, France. 7 Department of Digestive Surgery and Transplantation, CHU Lille, Univ Lille, 2 Avenue Oscar Lambret, 59037, Lille Cedex, France. 8 Department of hepato-gastroenterology, Rouen University Hospital, Normandie Univ, UNIROUEN, Inserm U1245, IRON group, F-76000 Rouen, France. 9 Department of Pathology, Normandy University, INSERM 1245, Rouen University Hospital, F 76 000 Rouen, France. 10 Department of Pathology, MESOPATH-MESOBANK, Centre León Bérard, Lyon, France. 11 Thoracic Oncology Department, CIC1425/CLIP2 Paris-Nord, Hôpital Bichat-Claude Bernard, Paris, France.
    [Show full text]
  • Coexistence of Eph Receptor B1 and Ephrin B2 in Port-Wine Stain Endothelial Progenitor Cells Contributes to Clinicopathological Vasculature Dilatation
    Coexistence of Eph receptor B1 and ephrin B2 in port-wine stain endothelial progenitor cells contributes to clinicopathological vasculature dilatation W. Tan iD ,1 J. Wang,1,2 F. Zhou,1,2 L. Gao,1,3 R. Yin iD ,1,4 H. Liu,5 A. Sukanthanag,1 G. Wang,3 M.C. Mihm Jr.,6 D.-B. Chen7 and J.S. Nelson1,8 1Department of Surgery, Beckman Laser Institute and Medical Clinic; 7Department of Obstetrics and Gynecology; and 8Department of Biomedical Engineering, University of California, Irvine, Irvine, CA, U.S.A. 2The Third Xiangya Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan 412000, China 3Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an, 710032, China 4Department of Dermatology, The Second Hospital of Shanxi Medical University, Taiyuan 030001, China 5Shandong Provincial Institute of Dermatology and Venereology, Jinan, Shandong 250022, China 6Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, U.S.A. Summary Background Port-wine stain (PWS) is a vascular malformation characterized by progressive dilatation of postcapillary venules, but the molecular pathogenesis remains obscure. Objectives To illustrate that PWS endothelial cells (ECs) present a unique molecular phenotype that leads to pathoanatomical PWS vasculatures. Methods Immunohistochemistry and transmission electron microscopy were used to characterize the ultrastructure and molecular phenotypes of PWS blood vessels. Primary culture of human dermal microvascular endothelial cells and in vitro tube formation assay were used for confirmative functional studies. Results Multiple clinicopathological features of PWS blood vessels during the development and progression of the disease were shown. There were no normal arterioles and venules observed phenotypically and morphologically in PWS skin; arterioles and venules both showed differentiation impairments, resulting in a reduction of arteriole- like vasculatures and defects in capillary loop formation in PWS lesions.
    [Show full text]
  • Ephrinb3 Is an Anti-Apoptotic Ligand That Inhibits the Dependence Receptor Functions of Epha4 Receptors During Adult Neurogenesis
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Biochimica et Biophysica Acta 1793 (2009) 231–238 Contents lists available at ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbamcr EphrinB3 is an anti-apoptotic ligand that inhibits the dependence receptor functions of EphA4 receptors during adult neurogenesis Céline Furne a,1, Jerome Ricard b,1, Jorge Ruben Cabrera a, Laurent Pays a, John R. Bethea b, Patrick Mehlen a,⁎,2, Daniel J. Liebl b,⁎,2 a Laboratory Apoptosis Cancer and Development, CNRS UMR 5238, Center Léon Bérard, University of Lyon, Lyon, France b The Miami Project to Cure Paralysis and Department of Neurosurgery, University of Miami School of Medicine, Miami, FL, USA article info abstract Article history: Eph receptors have been implicated in regulating a diverse array of cellular functions in the developing Received 18 December 2007 nervous system. Recently, Eph receptors have been shown to promote cell death in adult germinal zones; Received in revised form 2 September 2008 however, their mechanisms of action remain ill-defined. In this study, we demonstrate that EphA4 is a new Accepted 15 September 2008 member of the dependence receptors family, which can initiate cell death in the absence of its ligand Available online 7 October 2008 ephrinB3. Upon removal of its ligand, EphA4 triggers cell death that is dependent on caspase activation as caspase inhibitors prevent cell death. EphA4 itself is cleaved by caspase-3-like caspase in the intracellular Keywords: Ephrin domain at position D773/774, which is necessary for cell death initiation as mutation of the cleavage site Eph receptor abolishes apoptosis.
    [Show full text]