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Home , Artemin, Cerberus (protein), Chordin, Cripto, Decorin, GFRA2 (gene)

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Nodal BMP-8 TGF-b Superfamily BMP-7 BMP-5 GDF-10 GDF-1 BMP-11 BMP-3 BMP-4 BMP-6 GDF-3

GDF-8 BMP-2 BMP-9

Activin/Inhibin βC GDF-7 Activin/Inhibin βE BMP-10

Activin/Inhibin βB GDF-5 GDF-6

Activin/Inhibin βA

BMP-15

GDF-9

MIS

TGF-β1 Inhibin α TGF-β2 TGF-β3

Neurturin GDNF -B Lefty-A

Persephin The TGF-b Superfamily The transforming beta (TGF-b) superfamily contains highly pleiotropic molecules that encompass diverse functions during - genesis and adult tissue homeostasis. Mammalian members of the TGF-b superfamily include TGF-b1,-b2,-b3, Activins, Inhibins, BMPs (bone mor- phogenetic ), GDFs (growth differentiation factors), GDNFs (glial derived ), Nodal, Lefty, and MIS (Müllerian inhibiting substance). Sequence profile analysis of the TGF-b superfamily members indicate that they have a close structural similarity, sharing approximately 25-40% amino acid sequence identity. TGF-b ligands are initially synthesized as precursor proteins that undergo proteolytic cleavage. The mature segments form active ligand dimers via a disulfide-rich core consisting of the characteristic “cysteine knot”. Although homodimers are considered the standard form, there are natural heterodimers with biological activity as well.

Chordin LAP TGF-β dimers Small latent TGF-β BMP dimers Large latent TGF-β Growth BMPR-II Factor R TGF-β RIII RGM Receptor LTBP TGF-β RII ECM BMPR-I TGF-β RI

P P SARA XIAP RAS Smad6/7 Smad7

TAB1 ERK P P Smad2/3 Smad1/5/8 Smad4 TAK1 Smurf Smad4 Smad1/5/8 P P Smad4 P P Smurf Smad2/3

Smad4 MAPK Signaling MAPK/ERK (p38, JNK) JUN FOS

Smad4 CoR Smad P Proliferation, Apoptosis, , CoA Differentiation, ECM Remodeling, Migration Transcription factors CoR = Co-Repressors CoA = Co-Activators

TGF-b ligands bind to heteromeric receptor complexes with serine/threonine kinase domains. Upon ligand binding, the type II receptor activates the type I receptor by phosphorylation of the GS region. The type I receptor phosphorylates a receptor-activated Smad (R-Smad) protein. Phos- phorylated R-Smads form a trimeric complex with the common Smad4, and this complex moves into the nucleus to interact with transcriptional co-activators or co-repressors. This signaling cascade that ultimately alters transcription and cellular responses is regulated at several levels. Co-receptors may associate with ligands and act as obligate cofactors (such as TGF-b RIII for TGF-b2) enabling , or act to enhance signaling by increasing sensitivity to low ligand concentrations (such as RGM for BMP signaling). The particular type I-type II receptor combination, the activated Smad pathway, and the cell-specific transcription factors also offer diversity in responses. Contributions of accessory proteins such as soluble or membrane-bound regulators, and the use of Smad-independent signaling pathways further fine-tune TGF-b superfamily signaling and allow for disparate activities observed in response to TGF-b ligands in different contexts.

www.RnDSystems.com TGF-b-Related Products

ANTIBODIES ANTIBODIES ELISAs/ ELISAs/ MOLECULE PROTEINS ASSAYS MOLECULE PROTEINS ASSAYS POLYCLONAL MONOCLONAL LABELED POLYCLONAL MONOCLONAL LABELED

Activin A H M R H M R H M R H M R H M R CRIM1 H M H H H

Activin AB, AC H H M H M H M H M H Cryptic H H M H M H M Activin B H H CV-2 H M H M H M H M Activin C H M H M DAN H M H M H M H M H M Activin RIA/ALK-2 H H H H D D D Activin RIB/ALK-4 H M H M H M H H M H M H M H M H M Activin RIIA H H H H H Activin RIIB H M H H H /CD105 H M P H M H M H M H M ALK-1 H M H M H M H M M FLRG H M H M H M H M H ALK-7 R R R R H M H H H H Artemin H M H M H M H M Follistatin-like 1 H M H M R H M BAMBI/NMA H M H M Follistatin-like 4 H H H BMP-1/PCP H H H H GASP-1/ BMP-2 H Z H H Z H H M R WFIKKNRP H H H H H

BMP-2/7 GASP-2/WFIKKN H H H H H Heterodimer H H GDF-1 M M BMP-3 H H H H GDF-3 H M M M M BMP-3b/GDF-10 H H GDF-5 M M M M BMP-4 H M Z H H Z H H GDF-6 M BMP-4/7 Heterodimer H GDF-7/BMP-12 M M M BMP-5 H M H H H H GDF-8 Propeptide M M H M R M BMP-6 H M H H H H GDF-8/ H M R H M R H M R H M R BMP-7 H M H H H H GDF-9 M M M BMP-8 H H H GDF-11/BMP-11 H BMP-9 H M H H H H GDF-15 H H H H H BMP-10 H M H H H GDNF H R H R H H R H BMP-15/GDF-9B H H H M H GFRa-1 H R H R H R H R BMPR-IA/ALK-3 H M H H H GFRa-2 H M H M H H M BMPR-IB/ALK-6 H M H H M H GFRa-3 H M H M H H M BMPR-II H H H H GFRa-4 H M H M M Caronte Ch Ch Ch Ch H M M M CD109 H H H H Lefty H M H M H M H M 1 M H M H M H M MIS/AMH H H R H M R M M M M M MIS RII H R H R H Chordin-Like 1 H H H H H M H M H H M Chordin-Like 2 M H M H M H M Nodal H M M M M COCO H M H M H M H M H Noggin H M M M M

For a complete & up-to-date listing, visit www.RnDSystems.com/go/TGFbeta

For research use only. Not for use in diagnostic procedures. ANTIBODIES ELISAs/ MOLECULE PROTEINS ASSAYS POLYCLONAL MONOCLONAL LABELED

NOMO H

Persephin H M H M H M H

PP2Ca/PPM1A H H M R

PRDC M M M M M

Ret H M H M H M H M H BMP-15/GDF-9b in Mouse Ovary. Bone Morphoge- Twisted (TSG) Expression in netic Protein-15 (BMP-15) was detected in a frozen section Embryonic Mouse Ribs. Detection of TSG in a Phospho-Ret H (Y905) of adult mouse ovary using Human BMP-15 Monoclonal cryostat tissue section of mouse embryonic (15 d.p.c.) rib Antibody (Catalog # MAB2925). Cells were stained using cartilage primordium using Mouse Twisted Gastrulation Phospho-Ret (Y1062) H NorthernLights-557-conjugated Anti-Rat IgG Secondary Antigen Affinity-purified Polyclonal Antibody (Catalog # Antibody (red; Catalog # NL013). Nuclei were counter- AF756). Tissues were stained using Rhodamine Red™ X- SKI H stained with DAPI (blue). conjugated anti-goat secondary antibody (red) and coun- terstained with Fluoro Nissl Green (green). Smad1, 5, 8 H

Smad2 H M H H

Smad3 H M H H H GDNF Antibody (µg/mL) .01 0.1 1 Phospho-Smad3 0.32 (S423/S425) H

Smad4 H H H H 0.28 Smad7 H M R

SOST/Sclerostin H M H M H M H M 0.24 Relative Cell Number Cell Relative TGF-b1 H P Ms Ms Ms H M R Ca P 0.20 LAP (TGF-b1) H H H H M 0 0.1 1 10 BMPR-II in Mouse Embryo. BMPR-II was detected in a Recombinant GDNF (ng/mL) frozen section of E15 mouse ribs using Human BMPR-II Latent TGF-b1 H H Antigen Affinity-purified Polyclonal Antibody (Catalog # GDNF-induced Neuronal Survival and AF811; green). TGF-b1.2 H Ms Antibody Neutralization. Chick DRG neuron sur- vival increases in response to Recombinant Human GDNF TGF-b2 H P Ms Ms Ms H (Catalog # 212-GD) in a dose-dependent manner (blue line) as measured with the MTT Cell Proliferation/Viability Assay TGF-b3 H Ms Ms Ms H 80 (Catalog # TA5355). Neuronal survival elicited by 10 ng/mL 70 TGF-b5 A Ms GDNF is neutralized (green line) by increasing concentra- tions of Human/Rat GDNF Antigen Affinity-purified Poly- 60 Latent TGF-b bp1 H H clonal Antibody (Catalog # AF-212-NA). 50 Latent TGF-b bp2 H 40 Latent TGF-b bp4 M 30 TGF-b RI/ALK-5 M H M H M H M Number Cell Relative 20 M.W. Reduced Non-Reduced TGF-b RII H M H M H M H M H (kDa) 10

TGF-b RIIb H H 0 0 1 2 3 4 29 < BMP-2/7 10 10 10 10 10 TGF-b RIII H M H M H H M H Heterodimer TGF-β-1, -β2, -β3

TMEFF1/ 21 Tomoregulin-1 H M H M 18.4 Detection of TGF-b in PC-3 cells using TSG M M M M < BMP-7 Flow Cytometry. Intracellular staining of human 12.4 PC-3 prostate cancer cells with APC-conjugated Human TGF- TSK H < BMP-2 b1, -b2, -b3 Monoclonal Antibody (Catalog # IC1835A, filled histogram) or APC-conjugated Mouse IgG Isotype Vasorin/ 1 SLIT-like 2 H H H Control (Catalog # IC002A, open histogram). Recombinant BMP Heterodimer. Recombi- KEY: H: Human M: Mouse R: Rat A: Amphibian B: Bovine Ca: Canine Ch: D: Drosophila nant Human BMP-2/BMP-7 protein (Catalog # 3229-BM) is Ms: Multi-species P: Porcine Z: a refolded disulfide-linked heterodimer. Under reducing conditions the heterodimer separates into monomers as revealed by SDS-PAGE.

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www.RnDSystems.com Receptor & Smad Preferences

REGULATING MOLECULES CO-RECEPTORS TGF-βs MOLECULE TGF-bs TGF-β molecules are normally secreted as an inactive, latent complex. An N-terminal latency-associated (LAP) and a C-terminal mature TGF-β TYPE II R TGF-b RII a-Macroglobulin, BAMBI/NMA, monomer forms disulfide-linked homodimers that are non-covalently , BMP-1 ,Cripto, Decorin, associated after secretion, forming the small latent TGF-β1 complex. Cova- TYPE I R ALK-5 ALK-1,-2 Dermatopontin, KCP/Crim 2, LAP, LTBPs, Tolloid, Vasorin lent linkage of LAP to one of three latent TGF-β binding proteins (LTBPs) R-SMAD creates a large latent complex that may interact with the extracellular ma- Smad2/3 Smad 1/5/8 Betaglycan, Endoglin, CD109 trix. LTBP may facilitate secretion, stability, and/or targeting of latent TGF-β. Biological­ly active TGF-β requires release from the latent complex by the actions of proteases and . Virtually all cell types secrete the three MOLECULE Activins mammalian isoforms, TGF-β1, TGF-β2, and TGF-β3. TGF-β1.2 is a heterodi- TYPE II R Act RIIA/IIB mer of TGF-β1 and TGF-β2. Activin AC/BC/AE/CE, BAMBI/NMA, TYPE I R ALK-4 ALK-1,-2 Cripto, DAN, FLRG, Endoglin, Follistatin, Inhibin, KCP/CRIM2 BMPs & GDFs R-SMAD Smad2/3 Smad1/5/8   BMPs were originally identified by their ability to induce ectopic bone and cartilage formation. Further studies indicate the BMPs regulate a variety of developmental processes, including growth, differentiation, apoptosis, MOLECULE BMPs BAMBI/NMA, BMP-1, Biglycan, chemotaxis, morphogenesis, and pattern formation. BMP-1 is an exception TYPE II R BMP RII Act RIIA/IIB Caronte, Chordin-like 1,2, – it is not a ligand, but a protease that regulates processing of some family Chordin: TSG, COCO, Cerberus, CV-2, members. Based on , most of the GDFs are character- TYPE I R ALK-2,-3,-6 ALK-4,-5 ALK-1,-2 CRIM1, Endoglin, FLRG, Follistatin, ized as part of the BMP subfamily. Many BMPs and GDFs have alternate Gremlin, KCP/CRIM2, Noggin, names: R-SMAD Smad1/5/8 Smad2/3 Smad1/5/8 PRDC, SOST, TSK, USAG-1 RGM-A, -B, -C Ligand Alternate Name(s) Ligand Alternate name(s) Ligand Alternate name(s) BMP-2 BMP-2a BMP-8 Op-2, BMP-8b BMP-15 GDF-9b BMP-3 Osteogenin BMP-9 GDF-2 BMP-16 Nodal MOLECULE GDFs BMP-3b GDF-10 BMP-11 GDF-11 GDF-3 Vgr-1 TYPE II R BMP RII Act RIIA/IIB BMP-1, DAN, Follistatin, BMP-4 BMP-2b BMP-12 GDF-7, CDMP-3 GDF-8 Myostatin Propeptide (GDF-8, -11); BMP-6 Vgr-1 BMP-13 GDF-6, CDMP-2 GDF-15 Myc-1 TYPE I R ALK-5 ALK-3,-6 ALK-4,-5 ALK-6 GASP-1, -2, Lefty BMP-7 Op-1 BMP-14 GDF-5, CDMP-1 R-SMAD Smad2/3 Smad1/5/8 Smad2/3 Smad1/5/8 Cripto Activins & Inhibins MOLECULE Nodal Activins and Inhibins were originally purified from gonadal fluids as proteins that stimulated or inhibited, respectively, follicle stimulating hormone (FSH) TYPE II R Act RIIA/IIB release. Activins are homodimers or heterodimers of the various β subunit Cerberus, DAN, Lefty, TMEFF1 TYPE I R ALK-4,-7 isoforms, while Inhibins are heterodimers of a unique α subunit and one of Cripto the various β subunits. Four mammalian beta subunits (β , β , β , and β ) R-SMAD A B C E Smad2/3 have been cloned to date. The Activin/Inhibin nomenclature reflects the subunit composition of the proteins: Activin A (βA-βA), Activin B (βB-βB),

Activin AB (βA-βB), Inhibin A (α-βA), etc. MOLECULE MIS

TYPE II R MIS RII GDNFs

TYPE I R ALK-2,-3,-6 The GDNF subfamily consists of GDNF, Persephin, Artemin, and Neurturin. Members of this subfamily promote the survival of various neuronal popula- R-SMAD Smad1/5/8 tions in both the central and peripheral nervous systems at different stages of development. Most signaling of the GDNF subfamily is mediated by a re- ceptor complex composed of a high affinity ligand binding component, GFRα1-4, and a common signaling receptor , Ret. Other Ret- Alternate Names for Type I Receptors independent signaling pathways include the use of neural cell adhesion Type I Receptor Alternate name(s) molecule (NCAM), via a direct interaction with GFRα1, or indirect activation ALK-1 ACVLR1 of the , MET. ALK-2 Activin RIA Ligand/receptor preferences for the GDNF subfamily. ALK-3 BMPR-IA GDNF GFRα1-Ret, GFRα2-Ret, GFRα1-NCAM ALK-4 Activin RIB, ACVR1B Neuturin GFRα2-Ret, GFRα1-Ret ALK-5 TGF-β RI Artemin GFRα3-Ret, GFRα1-Ret ALK-6 BMPR-IB Persephin GFRα4-Ret ALK-7 ACVR1C

For research usewww.RnDSystems.com only. Not for use in diagnostic procedures. Literature Available from R&D Systems Award Winning Posters Scientific information artistically rendered. UNLEASH THE POTENTIAL OF STEM CELLS Embryonic stem (ES) cells derived from the inner cell mass of the blastocyst exhibit the remarkable capacity to diff erentiate into all cell types of the body. ES cells are capable of unlimited, undiff erentiated proliferation in vitro, while still maintaining the capacity for development into a wide variety of somatic and extra-embryonic tissues. The integration of a vast array of environmental cues and signal transduction events orchestrates these Epithelium processes. Recently it has been shown that adult cells can adopt a phenotype similar to ES cells by the introduction of a discrete subset of transcriptional ECTODERM Cutaneous Immunology regulators. Although more is yet to be learned, these induced pluripotent stem (iPS) cells show great promise as an alternative source for ES-like cells. Much research is focused on studying the factors that regulate ES/iPS cell diff erentiation with the hope that in the future these cells might be commonly used for therapeutic purposes. Part of this research includes the ability to identify each distinct lineage. Most often, the exquisite sensitivity of antibodies is used to assess the expression of markers specifi c for a given cell type. This illustration highlights a range of markers expressed as Surface Ectoderm pluripotent stem cells develop along ectodermal, mesodermal, and endodermal lineages. TP63 & Infectious Disease Neural Stem CeCellslls The response to infection is crucial for the survival of an organism. It includes a complex cascade of immunological events involving an array of cell types and the integration of a multitude of biochemical signals. This illustration depicts early CELL SURFACE INTRACELLULAR ABCG2 BMI-1 NeuroD1 infl ammatory processes that accompany insult of the epidermis by a sliver contaminated with the bacteria, Staphylococcus aureus. This is shown in contrast to normal tissue surveillance and the accompanying cellular migration patterns that CD133 Brg1 Nucleostemin enable the immune system to detect the introduction of pathogens. CXCR4 FABP7 SOX1 & 2 Neuron FGF R4 Mash1 Vimentin Adult Cells Frizzled-9 Musashi-1 & -2 Glut1 Nestin Epidermal Stem Cells IMMUNE CELL MARKERS α6high Type I Type II 6-Sulfo LacNAc In ammatory Monocyte-derived Immature Dermal Mature Dermal NG2/MCSP   Macrophage Macrophage Dendritic Cell Classic Monocyte Monocyte Langerhans Cell Dendritic Cell Dendritic Cell Dendritic Cell CD7low New! (IL-4-induced) (Slan DC) (Mono-DC) (DDC) (DDC) CD1a– CD1c+ 6-Sulfo LacNAc+ CCR1+ CCR2– Birbeck granule+ CD1a+ CD1a – CCR2+ CD1c– CD14+/– C5aR+ CCR2+ CCR5+ CCR6+ CD11c+ CD1c+ CD1a+ KLF4 + CD80+/– CD1a+ CD14+ CD11c+ CD1a+ CD14 CD83– CD1c+ CD14 low SOX2 Radial Glial Cells Neuron-Restricted Glial-Restricted Motor Neuron Progenitors + – – – – + – + c-Myc CD71+ CD86 CD1c CD16 CD14 DC-SIGN/CD209 CD86 DC-LAMP/CD208 CD83 Epithelial Cells Nanog Nestin Progenitors Progenitors Islet-1 & 2 CD80+ Integrin aVb5+ CD11c+ CD64+ CD16+ E-Cadherin+ DC-SIGN/CD209+ FXIIIa+ CXCR4+ Oct-3/4 RC1 & 2 Doublecortin A2B5 Lhx3 CD46 CEACAM-1 + – + + – + + – LIN-28 S100B NCAM FGF Receptors Neurogenin-2 CD86+ MMR/CD206 CD14 CXCR4 CXCR4 FXIIIa MHC II DC-SIGN/CD209 DC-SIGN/CD209 Vimentin MAP2 Nestin Olig2 8 Integrin aVb5– CD16+ TLR1+ TLR1+ Langerin/CD207+ MMR/CD206+ Langerin/CD207– FXIIIa+ βIII-Tubulin Cytokeratin 14 EpCAM – + + + – + + – Embryonic Stem Cells/iPS Cells MMR/CD206 PSGL-1 TLR2 TLR2 MMR/CD206 TLR1 MHC II Langerin/CD207 I/II III VIc VId Prostasin TLR2+ MMR/CD206+ MHC II+ 1* 19-22 2* 220-320 3* / 13-18 4* / / 12 / TLR2+ MMR/CD206– 99 80-92 100 99 Diff erentiated Post- OligodendrocOli yte- Type 1 Astrocyte Mitotic Neuronal Cells Type-2 CD44 TLR4+ TLR2– Shh Notch-1-4 BMP-2 TGF-b1 NeuN AsAstrocyte (0-2A) FGF R3 NOTES: Sonic Hedgehog Neurogenic Notch Bone Morphogenetic Transforming Growth GFAP Periodic Table of Human Developmental Factors Neurofi laments (e.g. NF-L, NF-M) Precursors Most common circulating DC phenotype; function unknown. RBC/CD47:SIRPa interaction keeps circulating DCs in an immmature state. Homolog Protein Protein 2 Factor beta 1  Glast 90% of circulating monocytes. Neurotransmitter Synthesizing (e.g. GAD, TH) A2B5  10% of blood monocytes. BMP-2A Ran-2 Synaptic Proteins (PSD-95, Synaptophysin, VAMP) Nestin Trophoblast S100B Patched 1,2 DLL1,3,4; Jagged 1, 2; DNER ALK-3,-6; BMPR-II; Endoglin; ALK-1,-2,-5; TGF-b RII,RIII; ZENON NG2/MCSP See Notes section below for Structure b CDX2 TGF- RIII; Act RIIA,RIIB Endoglin Olig1 & 2 IVa/b additional information VIb VIc VIc VIc Blastocyst Chorionic gonadotropin PLURIPOTENT STEM CELLS PDGF Rα * 19 * 140-180 * 17-18 The human developmental factors listed in the table include ligands and non-receptor, extracellular regulators of * 13-15 * 13 13-15 * 14 * 13-16 * 12 Cytokeratin 7 * 13-15 Observed Mature Molecular Weight (kDa) / / / / / CELL SURF/ ACE / /INTRACELL/ ULAR / EOMES 5 100 6 96 7 96 Note Number / / the major signaling pathways involved in . The molecules are presented in a tabular format 8 100 9 99 10 99 11 78 12 98 13 97 8 ABCG2 E-Cadherin DPPA5 Rex-1 EpCAM/TROP1 100 % Amino Acid Identity between mouse & human and color-coded according to family membership or regulatory activity. The information presented was obtained Alkaline Phosphatase Frizzled-5 FoxD3 Ronin TROP2 Ihh Jagged 1 FGF acidic Activin A Nodal GDF-5 GDF-1 (liver/bone/kidney)BMP-4 TGF-b2 from standard PubMed sources. Due to space constraints, this table does not include all possible modulators of the Integrin α6 GCNF/NR6A1 Smad2 Type 2 Astrocyte Oligodendrocyte Indian Hedgehog Jagged 1 Fibroblast Growth Inhibin bA chain Nodal Growth Differentiation Growth Differentiation CCR4Bone MorphogeneticIntegrin β 1 TransformingKLF2 Growth SOX2 Factor acidic Abbreviated Full Name represented signaling pathways and should not be considered definitive nor comprehensive. Factor 5 Factor 1 Protein 4 Factor beta 2 CD339 Activin A EDF BMP-16 CD9 PODXL/TRA-1-81 KLF5 STAT3 A2B5 GalC FGF-1; HBGF-1; ECGF BMP-14; CDMP-1 Vg1 CD24 BMP-2BSSEA-1 (mouse) LIN-28 SUZ12 CD44 MOG Inhibin b chain Complete Name CD30 GFAP Myelination Antigen Patched 1,2 Notch-1,-2,-3 FGF R1c,R2b,R2c,R3c A ALK-1,-2,-4; Act RIIA,RIIB; ALK-2,-4,-7; Act RIIA,RIIB ALK-6; Act RIIA,RIIB; BMPR-II; ALK-4,-7; Act RIIA,RIIB; ALK-3,-6; BMPR-II;SSEA-3 Act & RIIA;-4 (human) ALK-1,-2,-5;c-My TGF-c b RII,RIII TCF-3/TCF7L1 EDF Alternate Name Endoglin; TGF-b RIII TGF-b RIII Act RI; Nodal CD133 TGF-b RIIITRA-1-60 Nanog Tex19 Glast O1 V V V V V VIa Cripto-1 Oct-3/4 UTF10 Inner Cell Mass Musashi-1 O4 HematopoieticHematopoietic StStem Cells S100B SOX10 * 19 170-175 18 40-47 43-46 42 44-47 * 41-47 18-22 * 13-15 * 12-18 16 * 18 19-21 * 12 14 15 16 17 18 19 20 21 22 23 / 24 / 25 26 / 27 / 28 / / CELL SURFACE INTRACELLULAR 96 90 97 ALK-1,-2,-4; Act RIIA,RIIB; 99 96 95 99 96 93 97 100 99 83 96 100 ABCG2 CDCP1 BMI-1 Hiwi Endoglin; TGF-b RIII C1q R1/CD93 CXCR4 CDX4 HoxB4 Dhh Jagged 2 FGF basic Wnt-1 Wnt-2 Wnt-2b Wnt-3 Wnt-3a GDNF Activin B GDF-8 GDF-6 GDF-3 BMP-5 TGF-b3 CD34 Flt-3/Flk-2 ETV6/TEL Mcl-1 Desert Hedgehog Jagged 2 Fibroblast Growth Wingless/Int-1 type Wingless/Int-1 type Wingless/Int-1 type Wingless/Int-1 type Wingless/Int-1 type Glial cell-derived Inhibin-bB chain Growth Differentiation Growth Differentiation Growth Differentiation Bone Morphogenetic Transforming Growth CD44 PODXL GATA-2 PTEN Factor basic Protein 1 Protein 2 Protein 2b Protein 3 Protein 3a Neurotrophic Factor Factor 8 Factor 6 Factor 3 Protein 5 Factor beta 3 – + – Blood Vessel Receptors (or in the case of Regulators, Ligands) CD48 Sca-1 , Lin (mouse) GFI-1 STAT5 FGF-2; HBGF-2 Int-1 Wnt-13 ATF Myostatin BMP-13; CDMP-2 Vgr-2 CD133 SCR R/c-Kit Patched 1,2 Notch-1,-2,-3 FGF R1c,R2c Frizzled-1,-3,-8; Ryk Frizzled-1,-4,-5,-9 Frizzled-4,-5,-10 Frizzled-1,-7,-10; Ryk Frizzled-1,-2,-4,-5,-7,-8,-10+ GFRa-1,-2; Ret Act RIIA,RIIB; ALK-2,-4 Act RIIA,RIIB; proGDF-8 ALK-3,-6; BMPR-II ALK-4,-7; Act RIIA,RIIB Unknown Receptor ALK-1,-2,-5; TGF-b RII,RIII; CD150/SLAM VEGF R2/KDR/Flk-1 LRP-6; Ryk; ROR2 Endoglin IVc IVd IVe IVf * / 16-18/ * 85-95/ / 28-32 22 / 28-32 / 30 * 34 42-48 50-55 50-55 46-50 44-50 13 * 12-14 14-15 16 * / 16-17 22-24/ * 70-74 29 95 30 89 31 79 32 85 33 100 34 98 35 53 36 98 37 100 38 95 39 98 40 100 41 90 42 93 43 100 44 97 45 70 46 96 47 74 Smooth Muscle Progenitors HemangioblastHemangioblast Endothelial Progenitor Cells Endothelial Cells PDGF-A DLL1 FGF-3 FGF-4 FGF-8a FGF-9 FGF-19 Wnt-4 Wnt-5a Wnt-5b Wnt-6 Wnt-7a Neurturin Activin C GDF-11 GDF-7 BMP-15 BMP-6 MIS VE-Cadherin CELL SURFACE INTRACELLULAR CELL SURFACE INTRACELLULARULA CELL SURFACE INTRAINI TRRACCELLCELLULULARLAL – Platelet-derived Growth Delta-like 1 Fibroblast Growth Fibroblast Growth Fibroblast Growth Fibroblast Growth Fibroblast Growth Wingless/Int-1 type Wingless/Int-1 type Wingless/Int-1 type Wingless/Int-1 type Wingless/Int-1 type Neurturin Inhibin-bC chain Growth Differentiation Growth Differentiation Bone Morphogenetic Bone Morphogenetic Müllerian Inhibiting Caldesmin ACE/CD143 CD45 Brachyury VE-Cadherin CXCR4 vWF VE-Cadherin CXCR4 VCAM-1/CD106 vWF Factor A Factor 3 Factor 4 Factor 8a Factor 9 Factor 19 Protein 4 Protein 5a Protein 5b Protein 6 Protein 7a Factor 11 Factor 7 Protein 15 Protein 6 ENDODERMSubstance Calponin E-Cadherin– CD133 GATA-1 CD31/PECAM-1 MCAM/CD146 CD31/PECAM-1 MCAM/CD146 VEGF R1/Flt-1 PDGF-1 Int-2 K-FGF; Hst-1 AIGF GAF FGF-15 (mouse) BMP-11 BMP-12; CDMP-3 GDF-9b Vgr-1 AMH α-Smooth Muscle Actin VE-Cadherin EphB4 LMO2 CD34 SCF R/c-Kit CD34 SCF R/c-Kit VEGF R2/KDR/Flk-1 Smooth Muscle Myosin CD31/PECAM-1 PODXL RUNX1/CBFA2 CD45dim Tie-2 CD45 E-Selectin/CD62E PDGF Ra Notch-1,-2,-3 FGF R2b,R2c FGF R1c,R2b,R2c,R3c FGF R2c FGF R1c,R2c FGF R1c or R4+Klotho b Frizzled-6 Frizzled-1,-2,-3,-5,-7; ROR2 Unknown Receptor Frizzled-5+LRP-6;Frizzled-9,-10 GFRa-2,-1; Ret Act RIIA,RIIB Act RIIA,RIIB; ALK-4,-5,-7 ALK-3,-6; BMPR-II; Act RIIA ALK-6; BMPR-II; Act RIIA ALK-2,-3,-6; Act RIIA,RIIB; ALK-2,-3,-5-,6; MIS RII  -3; ROR2; BMPR-II Smooth Muscle Protein α-22 CD34 VEGF R2/KDR/Flk-1 SCL/TAL-1 CD133 VEGF R2/KDR/Flk-1 CD133 Tie-2 Frizzled-4+LRP-5; Ryk * / 14-16 * / 60 28 32-38 / 26-27 / 26 22 47-50 38-41 * 36 * 37 * 37 13 * 20 * 26 and 16 11-14 * / 20-22 * / 15-19/ * / 28 48 90 49 81 50 96 51 88 52 98 53 99 54 81 55 99 56 82 57 98 58 98 59 93 60 88 61 98 62 96 63 96 64 90Primitiv65 e Endoderm98 66 83Defi nitive β-Catenin Cerberus PDGF-B DLL3 FGF-7 FGF-5 FGF-17 FGF-16 FGF-21 Wnt-7b Wnt-8a Wnt-8b Wnt-9a Wnt-9b Artemin Activin E BMP-3 BMP-9 GDF-9 BMP-7α-Fetoprotein Lefty-A CXCR4 Platelet-derived Growth Delta-like 3 Fibroblast Growth Fibroblast Growth Fibroblast Growth Fibroblast Growth Fibroblast Growth Wingless/Int-1 type Wingless/Int-1 type Wingless/Int-1 type Wingless/Int-1 type Wingless/Int-1 type Artemin Inhibin-bE chain Bone Morphogenetic Bone Morphogenetic Growth Differentiation Bone MorphogeneticGATA-4 Lefty-A FABP1 & 2 Factor B Factor 7 Factor 5 Factor 17 Factor 16 Factor 21 Protein 7b Protein 8a Protein 8b Protein 9a Protein 9b Enovin; Neublastin Protein 3 Protein 9 Factor 9 Protein SOX7 7 Lefty-2; Ebaf α-Fetoprotein PDGF-2 KGF HBGF-5 Wnt-8d Wnt-14 Wnt-15; Wnt-14b Osteogenin; BMP-3A GDF-2 Op-1 GATA-4 HNF-3β PDGF Ra, Rb Notch-1 FGF R2b FGF R2c FGF R2c FGF R2c FGF R1c or R4+Klotho b Frizzled-1,-10 Frizzled-1,-8,-10 Unknown Receptor Unknown Receptor Unknown Receptor GFRa-1,-3; Ret Act RIIA,RIIB ALK-4; Act RIIB Act RIIA,RIIB; ALK-1,-2; ALK-5; BMPR-II Act RIIA,RIIB; BMPR-II; Cripto; Nodal BMPR-II; Endoglin ALK-3,-6 SOX17 Endothelial Cells * 18-22 80 30 25 / 31 / 28 * 32-33 * 42 * 43 48-54 * 37-43 * 14 13-14 * 18-53 11-12 11-13 * 13-15 * 16 * 28 67 94 68 87 69 94 70 93 71 99 72 95 73 72 74 96 75 98 76 98 77 92 78 95 79 67 80 80 81 97 82 99 83 68 84 70 85 86 PDGF-C DLL4 FGF-10 FGF-6 FGF-18 FGF-20 FGF-23 Wnt-10a Wnt-10b Wnt-11 Wnt-16b Norrin Persephin Inhibin a BMP-3b BMP-10 GDF-15 BMP-8 Lefty-B Platelet-derived Growth Delta-like 4 Fibroblast Growth Fibroblast Growth Fibroblast Growth Fibroblast Growth Fibroblast Growth Wingless/Int-1 type Wingless/Int-1 type Wingless/Int-1 type Wingless/Int-1 type Norrie Disease Protein Persephin Inhibin a Bone Morphogenetic Bone Morphogenetic Growth Differentiation Bone Morphogenetic Lefty-B Factor C Factor 10 Factor 6 Factor 18 Factor 20 Factor 23 Protein 10a Protein 10b Protein 11 Protein 16b NDP PSP Protein 3b Protein 10 Factor 15 PancreaticProtein 8Progenitors Lefty-1; BMP-18 Hepatic Endoderm SCDGF KGF-2 HBGF-6; Hst-2 Phosphatonin Wnt-12 GDF-10; BIP MIC-1;PLAB Op-2; BMP-8bHLXB9 C/EBP-β Activins FABP4 HAND1 TGF-βs HNF-6 GATA-4 BMP-2 FGF-5 MIXL1 Wnt-3a PDGF Ra Notch-1,-4 FGF R2b FGF R1b,R2b,R2c FGF R2c,R4 FGF R1c,R3b,R3c,R4 FGF R1c,R3c,R4+Klotho Unknown Receptor Frizzled-5 Frizzled-5,-7; Ryk Unknown Receptor Frizzled-4 GFRa-4; Ret TGF-b RIII; Act RIIA Unknown Receptor Act RIIA,RIIB; BMPR-II; Unknown Receptor Unknown Receptor Cripto; Nodal Brachyury Goosecoid Nodal Wnt-8a Bone ALK-1,-3,-6 NKX2.2 Hex NKX6.1 HNF-3β * 17-20 * 120-150 20-24 PDX-1 HNF-4α PTF1a HNF-6 86 91 87 91 88 80 LIMB BUD OUTGROWTH FAMILY KEY STRUCTURE KEY AnteriorSOX9 SP SP PDGF-D DNER FGF-22 I: Hedgehog Family IV: FGF Family, with subfamilies (a-f)‡ Monomer Proximal Distal Platelet-derived Growth Delta and Notch-like Fibroblast Growth 15 15 Posterior MesenchymalMesenchymal SStemtem Cellsells Factor D EGF-related Receptor Factor 22 FIRST STEP 16 SECOND STEP 16 THIRD STEP Homodimer Heterodimer FGF-10 Limb SCDGF-B BET Hepatic Progenitors CELL SURFACE INTRAINTRACCELLELLUULARLAR + – 17 FGF-10 Wnt-3a 17 FGF-10 Cytokeratin 19 BMP Receptors CD73 Sca-1 , Lin (mouse) Nucleostemin II: PDGF Family V: Wnt Family FGF-8 FGF-8 PDGF Rb Notch-1 FGF R2b / / / / / / FGF-8 Gremlin α-Fetoprotein CD29 CD90/Thy-1 SCF R/c-Kit Single Pass Transmembrane GPI Linked Soluble 18 18 FGF-8 Formin EndocrineBMP-2 Progenitors HGF R/c-Met CD44 CD105 STRO-1 FGF-8 FGF-4 – ‡ 19 19 Shh Islet-1 HNF-6 CD45 CD166 VCAM-1 III: Notch/DSL Family VI: TGF-b Family, with subfamilies (a-d) : GDNF, Activin, TGF-b, BMP/GDF Shh AER Pre-AER NeuroD1 Integrin β1 CD51 Integrin α1 Pre-ZPA ZPA 20 20 Neurogenin-3 OV-6 ‡ Subfamilies grouped according to amino acid identity, with a few exceptions that are listed according to function. 21 21 NKX2.2 Pref-1/DLK-1 IM LPM SE IM LPM SE Pax4 SP: Segmental Plate; IM: Intermediate Mesoderm; LPM: ; SE: Surface Ectoderm; ZPA: Zone of Polarizing Activity; AER: Apical Ectodermal Ridge Pax6 Islets of Langerhans CHONDROGENESIS Proliferating Chondrocyte * 45-47 83-88 * 31-35 * 24-26 * 23-34 * 130-135 * 120-130 * 45-50 33-36 * 24-30 22-32 * 37-39 * 78-80 * 65 MESENCHYMAL CONDENSATION / / / / / / / / Hepatocyte FGF 89 87 90 93 91 89 92 86 93 65 94 87 95 79 96 98 97 84 98 68 99 46 100 95 101 95 102 89 BMP Albumin α1-Antitrypsin Smo REGULATORS Gas1 HIP MAGP-1 MAGP-2 FGF-BP Klotho Klotho b Follistatin FLRG Cripto Cryptic TMEFF1 GASP-1 GASP-2 CD26 Ptc Growth Arrest Specific Hedgehog Interacting Microfibril-associated Microfibril-associated FGF Binding Protein Klotho Klotho b FSH-suppressing Protein Follistatin-related Cripto Cryptic Tomoregulin-1 GDF-associated Serum GDF-associated Serum Cyp3a4 Protein 1 Glycoprotein 2 HBp17 KL; Klotho-a KLB FS Gene Protein CR-1; TDGF-1; CFC-2 CFC-1 C9orf2 Protein 1 Protein 2 Cyp7a1 Ihh HHIP MAGP-1A; MFAP-2 MFAP-5; MP25 FSTL3; FSRP WFIKKNRP; WFIKKN2 WFIKKN; WFIKKN1 TAT FGF R Ihh; Shh Shh; Dhh; Ihh Notch-1; Jagged 1,2; DLL1 Notch-1; Jagged 1 FGF-1,-2,-7,-10,-22 FGF R1c,R3c,R4 FGF R1c,R2c,R3c,R4 Activin A; GDF-8,-11; Activin A; GDF-8 GDF-1,-3; Nodal; TGF-b1; GDF-1; Nodal Cripto-1 GDF-8,-11 GDF-8,-11 BMP-4,-5,-6,-7 Activin B; TMEFF-1; ALK-4 Myogenic Precursors Adipogenesis Chondrogenesis Osteoprogenitor Osteoblast BMP R Ihh Prehypertrophic Integrin α7 C/EBP-β and C/EBP-αhigh SOX9 Alkaline Phosphatase BAP Chondrocyte M-Cadherin I & II I BMP 26-34 * 110 60 52-55 * 130-140 * 140-150 * 80-90 48 * 26 24-27 24 20-23 34-42 * 22-26 * 26-32 * 29 / / / / Mrf-4 Decorin BMP 103 99 104 86 105 91 106 73 107 89 108 77 109 93 110 91 111 97 112 94 113 98 114 97 115 67 116 62 117 89 118 97 Myf-5 Chondrocyte MEPE IGFBP-3 MyoD Osterix Osteocalcin Hypertrophic Chondrocyte Noggin Chordin Chordin-like 1Chordin-like 2 CRIM1 CRIM2 CV-2 Brorin TSG DAN Gremlin PRDC Cerberus COCO SOST USAG Myogenin RUNX2/CBFA1 SPARC CHONDROGENESIS α Cells β Cells PP(γ) Cells δ Cells ε Cells CD44 Noggin Chordin Chordin-like 1 Chordin-like 2 Cysteine-rich Motor Cysteine-rich Motor Crossveinless-2 Brain-specific Chordin-like Twisted Gastrulation Differential Screening Gene Gremlin Protein Related Cerberus COCO SOST Uterine Sensitization- Pax3 Ghrelin Glut2 Pancreatic Polypeptide Somatostatin Ghrelin CD151 Bone Chrd CRDL1; Neuralin; Ventroptin CRDL2; BNF-1 Neuron 1 Precursor Neuron 2 Precursor CRIM3; BMPER Protein Aberrant in Neuroblastoma Drm, DAND2 to Dan & Cerberus DAND4; Cer1 Dante; Gremlin-3; Cer2; DAND5 Sclerostin associated Gene 1 Pax7 CRIM KCP; Kielin VWC-2 DAND1; NBL1 Gremlin-2; DAND3 Glucagon IAPP WISE; SOSTDC-1; Ectodin Collagens II & IV PCSK2 /Pro-insulin DSPG3 BMP-2,-4,-5,-6,-7; GDF-5,-6 BMP-2,-4,-7; TSG BMP-4,-4/7 BMP-2,-4,-6,-7; Activin A; TSG BMP-4,-7; TGF-b2; BMP-7; TGF-b1; Activin A BMP-2,-4,-5,-6 BMP-2,-6 BMP-2,-4; Chordin; TGF-b BMP-2,-4,-7; GDF-5 BMP-2,-4,-7; GDF-5 BMP-2,-4 Nodal; BMP-4 Nodal; BMP-4 BMP-2,-4,-6; LRP-5,-6 MAFA BMP-2,-4,-6,-7; LRP-6 Cardiac Muscle Sulfated Nodal; PDGF-B Cartilage PCSK1 & 2 Atrial Natriuretic Factor BMP-4 * 36-38 * 43 &70 * 54 & 32 * 190 * 210-220 * 180 * 215-225/ 105-110 /* 98 * 120-200 40-42 * 42-46 * 33-43 * 24 * 22 * 28-30 Cripto Osteocyte 119 94 120 93 121 83 122 91 123 80 124 87 125 89 126 84 127 80 128 97 129 90 130 84 131 92 132 71 133 92 134 97 Desmin Biglycan FABP3 Fibronectin CTGF Cyr61 NOV LTBP-1 LTBP-2 LTBP-3 LTBP-4 Vasorin Decorin Biglycan TSK SPARC SPP24 Dermatopontin CTHRC1 GATA-4 SPARC Growth Cysteine-rich, Nephroblastoma Latent TGF-b Binding Latent TGF-b Binding Latent TGF-b Binding Latent TGF-b Binding Vasorin Bone Proteoglycan II Bone/Cartilage Asporin Tsukushi Secreted Protein, Acidic, Secreted Dermatopontin Collagen Triple Helix Repeat- MEF2C Factor Angiogenic Inducer 61 Overexpressed Gene Protein 1 Protein 2 Protein 3 Protein 4 SLIT-like 2 PG-S2; PG40 Proteoglycan I PLAP1 LRRC54; E2-induced gene 4 Cysteine-rich Phosphoprotein 24 TRAMP; EQ-1 containing Protein 1 Myosin Heavy Chain CORONARY VESSEL DEVELOPMENT Epicardial Cells CCN2; IGFBP-8 CCN1; GIG1 CCN3; IGBP-9 TGF-b Binding Protein 1 SLRR1A; PG-S1 ; BM40 Secreted Phosphoprotein 2 NMTC1 NKX2.5 Pre-Adipocyte α-Sarcomeric Actin C/EBP-α LRP-6; BMP-4; TGF-b1 TGF-b Notch-1; BMP-2 LAP; ECM proGDF-8; ECM proGDF-8; LAP; ECM LAP; ECM TGF-b1,2,3 TGF-b1; BMP-4 TGF-b1; BMP-4 BMP-2; TGF-b1 BMP-4,-7; Chordin; DLL1; PDGF-AB; PDGF-BB; BMP-2 Decorin; TGF-b; BMP-2 Frizzled-3,-5,-6; ROR2; TBX5 Nodal; FGF-8 TGF-b; FGF-2 Wnt-3a,-5a,-11 Troponin T EPITHELIAL * * * * * * * * * * FGF MESENCHYMAL 30-45 38-42 50-58 35-38 34-38 32-36 34-38 50-52 33 42-44 39-41 33 43 22 55-66 50 56-58 TRANSITION 135 88 136 96 137 82 138 76 139 97 140 99 141 94 142 94 143 97 144 94 145 89 146 97 147 90 148 84 149 82 150 92 151 89 BMP TGF-β Dkk-1 Dkk-2 Dkk-3 Dkk-4 sFRP-1 sFRP-2 sFRP-3 sFRP-4 sFRP-5 WIF-1 R-Spondin 1R-Spondin 2R-Spondin 3R-Spondin 4 Myocilin Kremen-1 Kremen-2 Epicardial- Dickkopf-1 Dickkopf-2 Dickkopf-3 Dickkopf-4 Secreted Frizzled Related Secreted Frizzled Related Secreted Frizzled Related Secreted Frizzled Related Secreted Frizzled Related Wnt Inhibitory Factor 1 Roof Plate-specific Roof Plate-specific Roof Plate-specific Roof Plate-specific Myocilin Kringle-coding Gene Kringle-coding Gene derived Cells TGF-β Protein 1 Protein 2 Protein 3 Protein 4 Protein 5 Spondin 1 Spondin 2 Spondin 3 Spondin 4 Marking Eye & Nose 1 Marking Eye & Nose 2 Skeletal Muscle FGF REIC TIGR SARP2; FrzA SARP1 FrzB FrpHE; FrzB2 SARP3; FRP1B Rspo1 Rspo2; Cristin-2 Rspo3; Cristin-1 Rspo4; Cristin-4 Krm-1 Krm-2 α-Actinin VEGF µ-Calpain PDGF LRP-5,-6; Kremen-1,-2 LRP-5,-6; Kremen-1,-2 LRP-5,-6; Kremen-1,-2 Wnt-1,-2,-3a,-5a; Wnt-1,-3a,-4,-5a Wnt-1,-3a,-8 Frizzled-1; Wnt-7a,-8 Wnt-5a,-11 Wnt-1,-4,-8; Frizzled-8 Wnt-1; LRP-6; Frizzled-5,-8; Wnt-1; LRP-6; Frizzled-8 Wnt-1; LRP-6; Frizzled-8 Unknown Receptor Frizzled-1,-7,-10; sFRP-1,-3; Dkk-1,-2; LRP-5,-6 Dkk-1,-2,-4 CD146 Frizzled-4,-6,-7 Kremen-1,-2 WIF-1 Dystrophin β-Enolase Myocardial Cells * Notes © 2009 R&D Systems, Inc. Adipocytes 1. Contains both palmitic acid and cholesterol; Multimerization is reported to occur due to hydrophobic 12. Forms heterodimers with BMP-5, -6, and -7, and a noncovalent heterodimer with GDF- 3 30. DLL1 undergoes Notch-like proteolytic processing to generate transcriptional activators 59. Molecular weight listed is the predicted value 77. Biomarker for congenital heart defects 92. MAGP-2 induces both Notch-1 and Jagged-1 ECD release; May form a multimer with ECM proteins 108. Enhances BMP signaling 124. Secretion is dependent upon covalent association with LAP; LTBP-3 has low association with the ECM 137. Acts intracellularly to promote Wnt-mediated signaling FABP3 interactions between cholesterol and palmitate adducts 13. Forms heterodimers with TGF-b1 and -b3; LAP dimer and TGF-b dimer are noncovalently associated 35. Regulates bile acid synthesis and release; Amino acid sequence identity listed is between human 61. Antagonizes Activin A, possibly by forming Activin AE heterodimers 78. Regulates in the ear and eye via the ; Disulfide-linked 93. Association of FGF-BP with HSPGs weakens HSPG attachment of FGFs and promotes their release; 109. Both enhances and inhibits BMP signaling; CV-2 is proteolytically cleaved to generate an N- and 125. Incorporated into the ECM 142. Acts as a circulating phosphonin (promotes phosphate excretion) with FGF-23 Integrin α7β1 2. Type I transmembrane heterodimeric protein of intracellular and extracellular fragments 14. Contains both palmitic acid and cholesterol; Only two sources for DHH: Sertoli and Schwann cells; FGF-19 and mouse FGF-15 62. Acts as a BMP antagonist homodimers oligomerize to form higher order structures FGF-BP enhances the mitogenic effects of FGFs a C-terminal fragment that form a disulfide-linked heterodimer 127. Secreted proteoglycan (SLRP) 143. Molecular weight listed is the predicted value b 3. Forms heterodimers with BMP-5, -6, and -7 Multimerization is reported to occur due to hydrophobic interactions between cholesterol and 42. Antagonizes Activin A, possibly by forming Activin AC heterodimers 64. Cannot form disulfide bonds; Forms a noncovalent heterodimer with BMP-15; Active GDF-9 80. Forms a disulfide-linked heterodimer with subunits 94. Alternative transcript produces a secreted form. Belongs to the glycosyl hydrolase 1 family 111. Enhances BMP binding to Chordin; Also promotes proteolysis of Chordin (to promote BMP activity) 128. Secreted proteoglycan (SLRP); Antagonizes or potentiates TGF-b signaling. 144. The WIF domain interacts with palmitic acid adduct on Wnts Skeletal Muscle MR4 b b palmitate adducts b Adipocyte 4. Forms a heterodimer with TGF- 2; LAP dimer and TGF- dimer are noncovalently associated 44. Percent amino acid (aa) identity does not include 17 aa insert in the mouse protein is phosphorylated; Dephosphorylated GDF-9 is inactive 83. A divergent member of the TGF- superfamily 95. Fundamental regulator of aging and calcium/phosphorus metabolism 116. Antagonizes Nodal and BMP 130. Antagonizes BMP activity; Forms a complex with BMP and Chordin; Percent amino acid identity 145. Potentiates Wnt signaling; Blocks LRP-6 internalization by binding Kremen 21. Glycosylation and palmitoylation are necessary for secretion and activity b MyoD Smooth Muscle Cells 5. Contains both palmitic acid and cholesterol; Multimerization is reported to occur due to hydrophobic 45. Cannot form disulfide bonds; Forms a noncovalent hererodimer with GDF-9; Active BMP-15 65. BMP-7 prosegment and mature form associate similar to LAP:TGF- ; Forms heterodimers with 84. BMP-8A and -8B are duplicate with 98% amino acid precursor identity; Molecular weight listed 96. FS-315 is the serum scavenger for Activin 117. Antagonizes Wnt and BMP activity; Mutations cause bone dysplasias listed is between rat & human 147. Potentiates Wnt signaling; Signals independently through LRP-6 Endothelial Cells interactions between cholesterol and palmitate adducts 23. Forms a heterodimer with Inhibin-b chain (Activin BC), Inhibin a chain (Inhibin B) or Inhibin-b is phosphorylated; Dephosphorylated BMP-15 is inactive. BMP-2,-4, and GDF-7 is the predicted value Adiponectin C A 98. Binds to Activin/ALK-4 or to Nodal/ALK-4 to generate low efficacy, signaling receptors 118. Antagonizes Wnt (by binding LRP) and BMP activity 131. ECM protein; Blocks/antagonizes VEGF and PDGF signaling chain (Activin AB) 148. Molecular weight listed is the predicted value Myogenin 6. Proteolytically processed in a Notch-like fashion to generate transcriptional activators; 47. The unprocessed mature form is biologically active 66. 42 kDa proprecursor is bioactive; 34 kDa form is inactive; 28 kDa form is active 85. 42 kDa proprecursor is bioactive; 34 kDa form is inactive; 28 kDa form is active 100. Regulates Nodal but not Activin signaling 119. Inhibits BMP activity; Promotes TGF-b1 activity 132. Highly phosphorylated ECM protein Both inhibits and potentiates Notch-1 activity 24. GDF-8 propeptide binds Act RII and mature GDF-8, blocking its activity 149. Activates the Wnt pathway ALBP 48. Forms a disulfide-linked homodimer and a disulfide-linked heterodimer with PDGF-A 67. PDGF-C is activated extracellularly 86. PDGF-D is activated extracellularly b b Myosin Light Chain 101. Possesses trypsin-inhibitory activity; Binds both the mature and prosegment of GDF-8 120. Intracellular form is 43 kDa; Secreted form is 70 kDa 133. ECM protein; Forms a complex with Decorin and TGF- , increasing TGF- activity 150. At high levels of LRP-5/6, Kremen-1 collaborates with Dkk-1 to antagonize Wnt signaling; 7. Forms a dimer when complexed with 26. Cannot form disulfide bonds; Forms a heterodimer with BMP-4; Acts as both a BMP inhibitor, 49. Only binds Notch in cis; will not activate Notch 73. Promotes phosphate excretion 87. Neuronal protein restricted to soma or dendrites FABP4 and an activator of the Nodal pathway (at high doses) 102. Possesses trypsin-inhibitory activity; Binds both the mature and prosegment of GDF-8 121. Secreted, cytoplasmic, and nuclear 134. Inhibits TGF-b signaling and enhances the interaction of Wnt:ROR2 complexes In the absence of Dkk-1, Kremen-1 maintains LRP-6 on the cell surface 8. Forms a disulfide-linked heterodimer with Inhibina chain (Inhibin A) or Inhibin-bB chain (Activin AB) Troponin I b b 57. Molecular weight listed is the predicted value 74. Molecular weight listed is the predicted value 89. Gas1 requires CDO for HH binding; Concentrates Shh on the cell surface 104. Isoforms are tissue-specific and display unique BMP-binding affinities 122. Secreted with or without LAP association 136. Antagonizes Wnt signaling when bound to Kremen-2, ; Without Kremen-2, activates LRP-6 Coronary Vessel 9. Forms a heterodimer with GDF-1 28. Forms a heterodimer with TGF- 2; LAP dimer and TGF- dimer are noncovalently associated Fatty Acid Transporter 58. Molecular weight listed is the predicted value 75. Blocks preadipocyte differentiation 91. MAGP-1 induces Notch-1 ECD release; May form a multimer with ECM proteins 107. Binds to BMP proprecursors intracellularly and inhibits BMP activity; Soluble form is 10-15 kDa 123. LTBP-2 does not associate with TGF-b; It is integrated into the ECM and serves as an adhesion substrate and Wnt signaling 11. Forms a heterodimer with Nodal 29. Forms a disulfide-linked homodimer and a disulfide-linked heterodimer with PDGF-B Glut4 Leptin Lipoprotein Lipase PPARγ2 PM094_PeriodicTable_SEPT R&D Systems, Inc., 1-800-343-7475, www.RnDSystems.com Smooth Muscle VE-Cadherin Calponin α-Smooth Muscle Actin

R&D Systems, Inc., 614 McKinley Place NE, Minneapolis, MN 55413 USA NOTE: This poster conveys a general overview and should be considered neither comprehensive nor defi nitive. The details of the process are understood to be subject to interpretation. © R&D Systems, Inc. 2010 R&D Systems, Inc., 1-800-343-7475, www.RnDSystems.com 1-800-343-7475, Fax 612-379-6580, www.RnDSystems.com Note: The information in this poster should neither be considered comprehensive nor de nitive. The particulars involved are understood to be subject to interpretation. © 2009 R&D Systems, Inc. PM102_stemcell_JUL

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R&D Systems Tools for Cell Biology Research™

Multi-Color Flow Cytometry Kits: APRIL DuoSet ELISA Development Th17 & Treg Mutiplex Kits for the Luminex® Platform ELISA Development Systems System

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For more information on these kits, or for system, especially in the regulation of B cell Human Panel 1 (Catalog # MEA001) is a amount of cytokine bound to each individual capture Animal-Free™ Recombinant Proteins 3 serum or EDTA plasma using Luminex® 600 a complete listing of available Multi-Color Flow di erentiation and survival.2 APRIL is produced at 96-well microplate-based multiplex immunoassay anti-body is produced. Plates can be read using technology. ž e kit includes a panel of 500 Cytometry Kits, please see our website at DuoSet IC (Intracellular) ELISA Development Systems high levels by neutrophils, monocytes, dendritic cells, that allows for the simultaneous quanti cation of several common chemiluminescence camera pre-mixed, color-coded microparticles coated 400 Polyclonal Antibodies 3-4 www.RnDSystems.com/go/MultiColorFlow. ANALYTE SPECIES CATALOG #*REAGENTS FOR PRICE and osteoclasts, and at lower levels by other cell types. It 8 cytokines in a single sample of cell culture super- systems.*  e Mosaic ELISA provides an excellent with antibodies that speci› cally recognize Eotaxin, 300 Analyte Concentration (pg/mL) 200 D promotes class-switch recombination and somatic natant, serum, or plasma. Each kit contains a alternative to performing multiple traditional ELISpot Kits & Development New Multi-Color Flow Cytometry Kits IFN-J, IL-1E, IL-2, IL-5, IL-6, IL-8, Total ER /NR3A1 HumanDYC5715-2 2 Plates $325 microplate that has been pre-spotted in each well ELISA experiments. Modules 4 100 hypermutation activity in B cells, and is a survival KIT TYPE MARKERS CATALOG # IL-10, MCP-1, MIP-1E, or TNF-D. ž e captured Phospho-ErbB2 (Y1196) HumanDYC4438-2 2 Plates $325 0 factor for plasma cells. with antibodies that speci cally recognize CD40L, analytes are subsequently detected using a cocktail IL-2 Eotaxin IFN-J TNF-D MCP-1 IL-8 Total ROR1 HumanDYC2000-2 2 Plates $325 For more information and instructional videos, please Mouse ž 17 4-color • CD4-APC FMC008 IFN-J, IL-1D, IL-1E, IL-6, IL-8, IL-17, and TNF-D. visit our website at www.RnDSystems.com/go/Mosaic. Quantikine® ELISA Kits 5 • CCR6-Fluorescein of biotinylated detection antibodies and a Total ROR2 HumanDYC2064-2 2 Plates $325 Overexpression of APRIL has been linked to Utilizing the speci city of the traditional two-site • IL-22-PE Simultaneous Measurement of Multiple Primate Cytokines in Serum streptavidin-phycoerythrin (PE) conjugate. A dual *Also available in 5 plate packs for $645 and 15 plate Economy Packs for $1390. malignancies and autoimmune diseases. Unregu-lated FEATURES • IL-17-PerCP laser microparticle analyzer, such as the Luminex Samples. The concentrations of multiple proteins were simultaneously APRIL expression is associated with tumor progression, Cell-Based ELISA Kits 5 assessed in samples of normal primate serum using the Primate Fluorokine Human Treg 3-color • FoxP3-APC FMC013 ™ Analyte Format 96-well microplate 200 , is used to determine the color of each bead MultiAnalyte Pro ling 11-Plex Kit (Catalog # LKT006). Data are presented as and measurement of cytoplasmic APRIL mRNA or • CD25-PE 3 Microplate Well Analytes 8 per well and the magnitude of the PE-derived signal, which the mean ± the standard deviation (n=30). IL-2 and IFN-J were detected in protein can serve as a biomarker for some tumor types. • CD4-PerCP Monoclonal Antibodies 6 8% of the samples, TNF-D was detected in 15% of the samples, and Eotaxin, Data points per plate 320 data points in duplicate is proportional to the amount of analyte bound. Elevated levels of APRIL have been observed in the Light Mouse Treg 3-color • FoxP3-APC FMC014 MCP-1, and IL-8 were detected in greater than 95% of the samples. cerebrospinal  uid of patients with systemic lupus • CD25-PE For more information, please visit our website at HRP Sample size 25 µL B erythematosus (SLE) and in the serum of patients with Streptavidin-HRP DNA Damage & Repair Kits 6 • CD4-PerCP www.RnDSystems.com/go/PrimatePanel. Assay time 4.5 hours 4-6 Biotin-Conjugated Detection Antibody Cell Culture & Stem Cell Kits systemic sclerosis or Sjögren’s syndrome. Detection system Chemiluminescence-capable camera* MagCellect™ Cell Selection & 104 Specic Capture Antibody R&D Systems DuoSet ELISA Development Kits come with Detection Kits 6 PRODUCT SPECIES CATALOG # SIZE PRICE su cient reagents for 15, 96-well microplate assays. MEA001 Well Map Standard Curve Directed In Vivo Mouse 3450-048-K 1 Kit $550 A. 103 Biotinylated Antibodies 7 Angiogenesis Assay Kit CD40L IFN-J IL-1D Pluripotent Stem Cell 3-Color Human SC021 1 Kit $425 10 xP3 2 Immunocytochemistry Kit

IL-1E IL-6 IL-8 Fo 10

Treatment Time y Fluorochrome-labeled Antibodies 8-9 For single-step ICC staining of SOX2, Oct-3/4, and Nanog APRIL Standard IL-17 TNF-D Reference Mesenchymal Stem Cell Functional Rat SC020 1 Kit $425 Culture Supernatant Spot (RS) Multiplex Kits for the Luminex® ExactaChIP™ 1 101 Identi cation Kit 0 hours 4 hours 7.5 hours 24 hours 48 hours 72 hours Platform 10 Immunoprecipitation Modules Includes adipogenic, chondrogenic, and osteogenic media supplements, as well as an antibody panel for identi cation

B. ExactaChIP™ Chromatin ted Optical Densit 0.1 IL-1D IL-1E IL-6 100 R&D Systems ExactaChIP Chromatin Immunoprecipitation (ChIP) Modules contain a biotinylated antibody Immunoprecipitation Modules 10 0 1 2 3 4 10 10 10 10 10 orrec 500 6000 40000 in su“ cient quantity to process 20 samples for ChIP. Also included in the module are a negative control C 5000 35000 CD4 400 30000 antibody and primer pairs complementary to DNA regions known to associate with the transcription factor 4000 25000 300 ELISA Development Systems 11 104 0.01 3000 20000 or nuclear protein of interest. 3 4 5 200 10 10 10 2000 15000 10000 APRIL (pg/mL) 100 1000 Concentration (pg/mL) Concentration (pg/mL) Concentration (pg/mL) 5000 PRODUCT DESCRIPTION CATALOG # SIZE PRICE Protease Inhibitors 0 0 0 Cell Culture & Stem Cell Kits 11 3 047.5 24 48 72 047.5 24 48 72 047.5 24 48 72 10 APRIL Levels in Dilution Series. APRIL was detected using the Human APRIL/ E-Catenin Human MECP1329 1 Kit $395 TNFSF13 DuoSet ELISA Development System (Catalog # DY884). Plots show a two- Time (hours) Time (hours) Time (hours) ANALYTE SPECIES CATALOG # SIZE PRICE GLI-1 Human MECP3324 1 Kit $395 fold dilution series for Recombinant Human APRIL included as the kit standard

Protease Inhibitors 11 xP3 Simultaneous Detection of Multiple Analytes using the Mosaic ELISA Human Cytokine Panel. Human PBMCs were treated with 10 µg/mL PHA for 0-72 hours. 102 Phosphoramidon Multi-species EI006 5 mg $125 (black), and a 10X concentrate of conditioned media from THP-1 human acute Fo HIF-1D Human/Mouse MECP1935 1 Kit $395 Analytes were detected in the supernatant using the Mosaic ELISA Human Cytokine Panel 1 (Catalog # MEA001). A. The upper panel shows the well map and repre- monocytic leukemia cells stimulated for 4 days with 100 ng/mL PMA and 1 µg/mL New Antibodies for Th17 & Treg Cell Inhibits  ermolysin-like Metalloproteases including Neprilysin,  ermolysin, and Endothelin-converting . sentative images of individual wells for the standard curve and supernatants from PHA-treated PBMCs. PBMC supernatants were diluted 1:64 to ensure that the KLF4 Human MECP3640 1 Kit $395 retinoic acid in a serum-free environment (red). Research 12 values for all of the analytes fell within the standard curve. The Reference Spot (RS) provides a strong positive signal for easy visualization of the well locations. B. The 1 10 Nanog Human MECP1997 1 Kit $395 lower panel shows three examples of analyte quanti cation generated by analysis of the mean spot pixel densities of individual spots in each well. References Oct-3/4 Human/Mouse MECP1759 1 Kit $395 Mosaic ELISA Kits 1. Kimberley, F. et al. (2009) J. Cell Physiol. 218:1. 100 p53 Human/Mouse MECP1355 1 Kit $395 0 1 2 3 4 2. Bossen, C. & P. Schneider (2006) Semin. Immunol. PRODUCTCATALOG # SIZE PRICE 10 10 10 10 10 CD25 Smad4 Human MECP2097 1 Kit $395 18:263. Mosaic ELISA Human Cytokine Panel 1 MEA001 1 Kit $1,920 Assessment of the Human Treg Population by Multi-Color Flow Cytometry. SOX2 Human/Mouse MECP2018 1 Kit $395 3. Moreaux, J. et al. (2009) BMC Cancer 9:83. Human peripheral blood mononuclear cells (PBMCs) were stained with antibodies · CD40L · IFN-J· IL-1D · IL-1E · IL-6 · IL-8 · IL-17 · TNF-D 4. George-Chandy, A. et al. (2008) Arthritis Res.  er. included in the Human Regulatory T Cell 3-Color Flow Cytometry Kit (Catalog # STAT3 Human/Mouse MECP1799 1 Kit $395 10:R97. * Compatible imaging systems tested by R&D Systems include Quansys Biosciences Q-View™ Imager; Alpha Innotech FluorChem® HD2 and FC2; BioRad® Versa Doc™ 4000, and FMC013): FoxP3-APC, CD25-PE, and CD4-PerCP. Dot plots show the relative CD4+, ChemiDoc™ XRS; Fuji lm LAS-3000, LAS-3000 Mini, and Aushon BioSystems SearchLight® imager. + + et al. 34 FoxP3 , and CD25 cell populations. Quadrants were set based on isotype controls. Luminex is a registered trademark of Luminex Corporation. Luminex 200 is a trademark of Luminex Corporation. 5. Matsushita, T. (2007) J. Rheumatol. :2056.

www.RnDSystems.com 10 For research use only. Not for use in diagnostic procedures. www.RnDSystems.com 11

Cytokine Bulletins Includes our BioBrief Take Away Reference Tool

R&D Systems Tools for Cell Biology Research™ R&D Systems Tools for Cell Biology Research™ The IL-12 Family of Cytokines & Mechanisms of Intestinal Inflammation Dietary Antigens INTESTINAL HOMEOSTASIS TGF-E, KGF MECHANISMS THAT DISRUPT INTESTINAL HOMEOSTASIS Bacterial Invasion Intestinal Lumen Commensal Microora Anti-microbial : DET Cell Pathogenic Microbes Goblet Cells 2010 | Issue 2 · RnDSystems.com 2010 | Issue 2 · RnDSystems.com Defensins, RegIIIJ JGT Cell Toll-Like Receptor (TLR) RELME, Angiogenin 4 ˆ Peyer’s Patch Mucus Bacterial Attachment IgA2 Breakdown of Intestinal Barrier Function Isolated TLR Increased Leakage Lymphoid The IL-12 Family of Cytokines Regulates Follicle Trefoil Peptides Plasma Cell Tight Junctions Inflammation l Inflammation T Cell-Mediated Pro- & Anti-Infl ammatory TGF-E, TSLP, APRIL

™ s & Mechanisms of Intestinatary Antigens ology Research amily of Cytokine Die Tools for Cell Bi -12 F NAL HOMEOSTASIS R&D Systems The IL T DISRUPT INTESTI MECHANISMS THA Restitution/Proliferation TGF-β, KGF Intestinal Lumen AL HOMEOSTASIS Microfold Cells INTESTIN Bacterial Invasion Immune Responses Goblet Cells Mucus Isolated thogenic Microbes robial αβ T Cell Pa Lymphoid nsal Microora Anti-mic s Patch eakage Comme Peptides: γδ T Cell ˆ Peyer’ Increased L Follicle , RegIIIγ tion B Cell .com Defensins Func 2 · RnDSystems nin 4 of Intestinal Barrier Inflammation 2010 | Issue RELMβ, Angioge Breakdown Conditioned DC noic Acid Toll-Like Receptor (TLR) C TGF-β, TSLP, Reti E tions ed D TGF- , TSLP, Retinoic Acid IgA2 Tight Junc Condition Intestinal Epithelial Cells nt ells ates Bacterial Attachme Microfold C l Cells Cytokines Regul TLR ell Intestinal Epithelia L-12 Family of ry Mucins Plasma C Response to The I ammato & Anti-Infl Trefoil Peptides GF-β, TSLP, APRIL ina Propria DC ell-Mediated Pro- T ‰ Lam T C ion sponses n B Cell une Cell Reactivity T Cell Differentiat Immune Re Restitution/Proliferatio Altered Imm Regulatory Macrophage -6, TNF-α stinal im- IL-1β, IL ‰ ability of the inte sis relies on the Response to ed DC TGF-β, Retinoic Acid II Intestinal homeosta while providing gens Recruit Macrophage MHC mmensal micro ora, harmful anti IL-2 harmful antigens m to tolerate co normal Paneth Cells Conditioned DC β RII B7 mune syste obes. Under GF-β, Retinoic Acid ‹ β RI TGF- against invasive micr T TGF- Intestinal homeostasis relies on the ability of the intestinal im- protective immunity cells (DCs) pref- -27, TNF-α aired Regulation CD28 d dendritic Recruited DC IL-6, IL-23, IL Imp Treg Cells Rγ IL-2 Rβ Macrophage , gut-associate IL-2 TCR-CD3 Lamina Propria physiological conditions ry T (Treg) cells IL-35 entiation of regulato IFN-γ, TNF-α ells Š IL-35 induce the di er rrant IL-10 Th1 C s Rα/CD25 Jak1 d erentially to prevent abe eg Cells ctor T Cell IL-2 Sma nosuppressive cytokines IL-17 Tr Overproduction of Effe Altered Immune Cell Reactivity ete immu that ells that secr ganisms, or those IL-22 Th1 C IL-10 17 Cells  Jak3 . Pathogenic microor TGF-β Th STAT5 immune responses e in genetically nic but elicit a respons Tr1 Cells e typically nonpathoge ton and in- Th17 Cells IL-27 , TNF-α ar immune cell activa IFN-γ ible individuals, trigger the dif- Paneth Cells e ry mune system to tolerate commensal micro ora, while providing suscept promot ammato obes activate DCs that Anti-Infl Retinoic Acid STAT5 FoxP3 ammation. These micr h17 speci c ammatory β + a Th1, Th2, or T Pro-Infl IL-10 TGF- naïve CD4 T cells to ferentiation of s and DCs, secrete , IL-22 TGF-β IL-2 Conditioned DC g with macrophage -6, IL-17A, IL-17F . T helper cells, alon ive IL TGF-β RI Th0 Cell lineage at eliminating the causat RII ry cytokines aimed TGF-β pro-in ammato tion, altered im- tiation n IL-2 Rγ IL-2 Rβ intestinal barrier func ed DC Th1 Differen Th17 Differentiatio gen. Breakdown of or exag- Recruit patho ora, or inappropriate IL-23 ctivity to intestinal are IL-27 gp130 IL-21 γ IL-2 Rα/CD25 Jak1 mune cell rea fail to suppress, IL-2 R Smad protective immunity against invasive microbes. Under normal s that Treg cells IL-6 DC T cell response and tissue IL-21 R IL-23 R Jak3 Recruited DC gerated in ammation -1 IL-27 STAT5 can lead to chronic TCCR-WSX Rβ1 IL-6 Rα E that IL-12 TGF- , Retinoic Acid mechanisms el disorders such IL-12 β1 f in ammatory bow Jak1 Jak1 IL-12 R tion characteristic o disease Jak2 gp130 Jak2 xP3 destruc itis (–‘™). Crohn’s TGF-β RII 0 Tyk2 STAT5 Fo Recruited DC and ulcerative col Tyk2 -1 β gp13 as Crohn’s disease family cytokines Th0 Cell TCCR-WSX IL-12 R 1 ell E D IL-12 Treg C IL-1 , IL-6, TNF- egulation of IL-12 Rβ2 TGF-β RI AT5 iated with an upr es, along AT3 Jak1 STAT3 STAT4 1 ST is assoc terodimeric cytokin ST Tyk2 STAT FoxP3 and IL-23. These he Proliferation including IL-12 iation of Th1 and Jak2 R, IL-17 egulate the di erent -27 STAT1 Jak2 RORγt, IL-23 physiological conditions, gut-associated dendritic cells (DCs) pref- IL-35, r IL STAT4 Tyk2 Regulatory T Cell Differentiation with IL-27 and pro- and anti- T-bet STAT3 nteric ole in the balance of STAT3 Mese and play a crucial r have STAT3 STAT5 ymph Node Th17 cells, this reason, they STAT1 d Th0 Cell F, IL-22 L responses. For Sma RORγt IL-17, IL-17 in ammatory immune pathogenesis of TCR-CD3 GATA-3 for inhibiting the IFN-γ T-bet J D Macrophage l targets IFN- , TNF- become potentia Th17 Cell disorders. CD28 STAT3 IL-21 IL-21 in ammatory bowel T Cell Function MHCII B7 IFN-γ IL-6 tors Eff ect on T-bet TCR-CD3 Subunits Recep IL-27 IL-6 Rα Cytokine TGF-β IL-21 R IL-2 Rγ erentially induce the di erentiation of regulatory T (Treg) cells β 2 Rβ2 IL-12 R 1 IL-35 IL-1 Th1 Di erentiation CD28 30 p40 Promotes IL-12 Th1 Cell TGF-β RII gp1 p35 gp130 MHCII 30 IL-12 B7 gp1 IL-17 TLR D X-1 IL-6, IL-23, IL-27, TNF- CR-WS Jak1 IL-12 TC I Jak3 IL-1β IL-12 Rβ1 TLR TGF-β R IL-10 Jak1 -23 R IL-12 Rβ1 Jak1 IL h17 Di erentiation Jak1 IL-12 Rβ2 Promotes T Jak2 RI p19 p40 Jak2 Tyk2 IL-1 IL-23 Tyk2 STAT3 Mesenteric IL-6 Th17 Cell h1 Commitment Node STAT3 ad IL-1 RAcP Early T Lymph IL-23 Sm that secrete immunosuppressive cytokines to prevent aberrant IL-22 TCCR-WSX-1  erentiation gp130 Inhibits Th17 Di EBI3 tes a Trl-like Phenotype AT1 -23 R, IL-17 p28 Stimula ST STAT3 RORγt, IL TGF-E, Retinoic Acid -27 T Cells T-bet IL in E ector STAT1 Mesenteric Th1 Cells Lymph Node ‹ tes Treg Proliferation Unknown Promo β2 Recruited DC eg -bet IL-12 R EBI3 Enhances Tr T p35 pacity Treg Cells e Ca ell IL-35 Suppressiv Th1 C e Domain IL-2 n Fibronectin-lik ceptor Homology Domai in Cytokine Re MHCII oma immune responses. Pathogenic microorganisms, or those that Ig-like D e. Four α Helix Bundle ive nor de nitiv KEY: onsidered comprehens c literature and is not to be c ocesses suggested in the scienti Impaired Regulation esents general pr This illustration repr TGF-E CB103_issue2 IL-10 Th1 Cells E E are typically nonpathogenic but elicit a response in genetically Th17 Cells Š Treg Cells TGF- RI TGF- RII B7 susceptible individuals, trigger immune cell activation and in- IL-27 Tr1 Cells Overproduction of Effector T Cells IL-2 RJ CD28 IL-35 IL-2 RE The IL-12 Family of Cytokines  ammation. These microbes activate DCs that promote the dif- Th17 Cells  IL-2 RDCD25 TCR-CD3 & Mechanisms ferentiation of naïve CD4+ T cells to a Th1, Th2, or Th17 speci c Pro-Inflammatory Anti-Inflammatory Jak1 IFN-J, TNF-D Smad of Intestinal Infl ammation lineage. T helper cells, along with macrophages and DCs, secrete Jak3 pro-in ammatory cytokines aimed at eliminating the causative STAT5 Immune responses in the intestine are tightly pathogen. Breakdown of intestinal barrier function, altered im- regulated to maintain a delicate balance be- Recruited DC mune cell reactivity to intestinal  ora, or inappropriate or exag- Th1 Differentiation IL-6, IL-17A, IL-17F, IL-22 IL-10 Retinoic Acid tween cells that promote host defense and gerated T cell responses that Treg cells fail to suppress, are TGF-E STAT5 IL-27 gp130 TGF-E FoxP3 those that suppress in ammation. Disruption mechanisms that can lead to chronic in ammation and tissue IL-2 Th17 Differentiation of this balance can lead to chronic intestinal destruction characteristic of in ammatory bowel disorders such TCCR/WSX-1 TGF-E RI IL-27 as Crohn’s disease and ulcerative colitis (‰). While ulcerative Jak1 Jak1 IL-12 RE1 IL-2 RJ E TGF-E RII Th0 Cell in am mation characteristic of in ammatory IL-6 IL-21 IL-23 IL-2 R colitis has been linked with increased levels of IL-13 and an Th0 Cell Jak2 IL-12 IL-2 RJ bowel disorders. Although the molecular fac- Tyk2 D excessive Th2 response, Crohn’s disease is associated with an up- gp130 IL-6 RD IL-21 R IL-2 R CD25 Jak1 tors responsible for these disorders are not TCCR/WSX-1 IL-23 R regulation of IL-12 family cytokines including IL-12 and IL-23, STAT3 IL-12 RE1 Smad currently well-understood, four mechanisms Proliferation TGF-E RII Jak3 and increased Th1 and Th17 activities. IL-12 and IL-23 regulate IL-27 STAT1 IL-12 RE2 E STAT5 (‚) have been proposed to explain their Tyk2 TGF-E RI gp130 Jak2 IL-12 R 1 the di erentiation of Th1 and Th17 cells, and along with IL-27 T-bet STAT4 Jak1 Tyk2 pathogenesis. Each of these mechanisms leads and IL-35, play a crucial role in the balance of pro- and anti- Jak2 STAT3 STAT5 TCR-CD3 STAT4 FoxP3 to an inappropriate or exaggerated T cell re- STAT3 STAT1 STAT5 in ammatory immune responses. For these reasons, they have GATA-3 STAT1 STAT5 Jak2 sponse that promotes in ammation. Crohn’s become potential targets for inhibiting the pathogenesis of STAT3 Tyk2 Treg Cell RORJt, IL-23 R, IL-17 FoxP3 disease is associated with an upregulation of CD28 IFN-J Smad STAT3 in ammatory bowel disorders. MHCII B7 T-bet Th0 Cell IL-12 family cytokines including IL-12 and Cytokine Subunits Receptors Eff ect on T Cell Function RORJt IL-17, IL-17F, IL-22 Mesenteric IL-23. The IL-12 cytokine family, which also IL-27 T-bet J IFN- STAT3 IL-21 Lymph Node includes IL-27 and IL-35, play a critical role IL-21 TLR TCR-CD3 Th17 Cell in balancing T cell-mediated pro- and anti- IL-12 Promotes Th1 Di erentiation gp130 IL-12 TGF-E IL-12 TCCR/WSX-1 Th1 Cell IL-6 in ammatory immune responses. These prop- CD28 IL-21 R IL-12 RE1 MHCII IL-2 RJ IL-6 RD erties suggest that IL-12 family cytokines may Jak1 Jak1 B7 TGF-E RII gp130 play a key part in the regulation of intestinal IL-23 Promotes Th17 Di erentiation Jak2 IL-12 RE2 Mesenteric Tyk2 TLR TGF-E RI Jak1 gp130 homeostasis, and ultimately, the pathogene- Lymph Node Jak3 STAT3 IL-1E sis of in ammatory bowel disorders. Promotes Early Th1 Commitment Jak1 Inhibits Th17 Di erentiation STAT1 Jak2 IL-27 IL-6 Tyk2 IL-1 RI Stimulates a Tr1-like Phenotype Th17 Cell STAT3 in E ector T Cells STAT1 T-bet IL-23 Smad IL-1 RAcP Promotes Treg Proliferation T-bet IL-12 RE2 STAT3 IL-35 Enhances Treg Mesenteric RORJt, IL-23 R, IL-17 Suppressive Capacity Th1 Cell Recruited DC Lymph Node For additional copies of the BIObrief, please visit KEY: Four D Helix Bundle Ig-like Domain Cytokine Receptor Homology Domain Fibronectin-like Domain www.RnDSystems.com/go/BIObrief This illustration represents general processes suggested in the scienti c literature and is not to be considered comprehensive nor de nitive. CB103_issue2_MAY Request your FREE literature at www.RnDSystems.com/go/Request MA101_TGFbeta_AUG