KEGG   PATHWAY: hsa04350
Entry
hsa04350                    Pathway                                

Name
TGF-beta signaling pathway - Homo sapiens (human)
Description
The transforming growth factor-beta (TGF-beta) family members, which include TGF-betas, activins and bone morphogenetic proteins (BMPs), are structurally related secreted cytokines found in species ranging from worms and insects to mammals. A wide spectrum of cellular functions such as proliferation, apoptosis, differentiation and migration are regulated by TGF-beta family members. TGF-beta family member binds to the Type II receptor and recruits Type I, whereby Type II receptor phosphorylates and activates Type I. The Type I receptor, in turn, phosphorylates receptor-activated Smads ( R-Smads: Smad1, Smad2, Smad3, Smad5, and Smad8). Once phosphorylated, R-Smads associate with the co-mediator Smad, Smad4, and the heteromeric complex then translocates into the nucleus. In the nucleus, Smad complexes activate specific genes through cooperative interactions with other DNA-binding and coactivator (or co-repressor) proteins.
Class
Environmental Information Processing; Signal transduction
Pathway map
hsa04350  TGF-beta signaling pathway
hsa04350

Network
nt06118  TGFB signaling (viruses)
nt06160  Human T-cell leukemia virus 1 (HTLV-1)
nt06162  Hepatitis B virus (HBV)
nt06218  TGFB signaling
nt06260  Colorectal cancer
nt06261  Gastric cancer
nt06263  Hepatocellular carcinoma
nt06276  Chronic myeloid leukemia
  Element
N00063  TGF-beta signaling pathway
Drug
D00742  Etanercept (USAN/INN)
D01583  Pirfenidone (JAN/USAN/INN)
D02597  Adalimumab (USAN/INN)
D02598  Infliximab (USAN/INN)
D03441  Certolizumab pegol (USAN/INN)
D04358  Golimumab (USAN/INN)
D05146  Nerelimomab (USAN/INN)
D05263  Onercept (USAN/INN)
D05393  Pegsunercept (USAN)
D06563  Belagenpumatucel-L (USAN)
D07436  Afelimomab (INN)
D09014  Terameprocol (INN/USAN)
D09620  Fresolimumab (USAN/INN)
D09670  Sotatercept (USAN/INN)
D09944  Ozoralizumab (USAN)
D10437  Galunisertib (USAN)
D11701  Luspatercept (USAN/INN)
D11703  Opinercept (INN)
D11893  Bintrafusp alfa (USAN/INN)
Other DBs
GO: 0007179
Organism
Homo sapiens (human) [GN:hsa]
Gene
8646  CHRD; chordin [KO:K04657]
9241  NOG; noggin [KO:K04658]
4681  NBL1; NBL1, DAN family BMP antagonist [KO:K19558]
100532736  MICOS10-NBL1; MICOS10-NBL1 readthrough [KO:K19558]
26585  GREM1; gremlin 1, DAN family BMP antagonist [KO:K23318]
64388  GREM2; gremlin 2, DAN family BMP antagonist [KO:K23318]
7057  THBS1; thrombospondin 1 [KO:K16857]
1634  DCN; decorin [KO:K04660]
2331  FMOD; fibromodulin [KO:K08121]
10637  LEFTY1; left-right determination factor 1 [KO:K04668]
7044  LEFTY2; left-right determination factor 2 [KO:K04668]
10468  FST; follistatin [KO:K04661]
650  BMP2; bone morphogenetic protein 2 [KO:K21283]
652  BMP4; bone morphogenetic protein 4 [KO:K04662]
654  BMP6; bone morphogenetic protein 6 [KO:K16620]
3625  INHBB; inhibin subunit beta B [KO:K22687]
653  BMP5; bone morphogenetic protein 5 [KO:K04663]
655  BMP7; bone morphogenetic protein 7 [KO:K16621]
656  BMP8B; bone morphogenetic protein 8b [KO:K16622]
353500  BMP8A; bone morphogenetic protein 8a [KO:K16622]
8200  GDF5; growth differentiation factor 5 [KO:K04664]
392255  GDF6; growth differentiation factor 6 [KO:K20012]
151449  GDF7; growth differentiation factor 7 [KO:K20013]
268  AMH; anti-Mullerian hormone [KO:K04665]
79875  THSD4; thrombospondin type 1 domain containing 4 [KO:K23377]
2200  FBN1; fibrillin 1 [KO:K06825]
4052  LTBP1; latent transforming growth factor beta binding protein 1 [KO:K19559]
7040  TGFB1; transforming growth factor beta 1 [KO:K13375]
7042  TGFB2; transforming growth factor beta 2 [KO:K13376]
7043  TGFB3; transforming growth factor beta 3 [KO:K13377]
3624  INHBA; inhibin subunit beta A [KO:K04667]
3626  INHBC; inhibin subunit beta C [KO:K22688]
83729  INHBE; inhibin subunit beta E [KO:K22689]
4838  NODAL; nodal growth differentiation factor [KO:K04666]
4756  NEO1; neogenin 1 [KO:K06766]
148738  HJV; hemojuvelin BMP co-receptor [KO:K23100]
657  BMPR1A; bone morphogenetic protein receptor type 1A [KO:K04673] [EC:2.7.11.30]
658  BMPR1B; bone morphogenetic protein receptor type 1B [KO:K13578] [EC:2.7.11.30]
90  ACVR1; activin A receptor type 1 [KO:K04675] [EC:2.7.11.30]
659  BMPR2; bone morphogenetic protein receptor type 2 [KO:K04671] [EC:2.7.11.30]
92  ACVR2A; activin A receptor type 2A [KO:K04670] [EC:2.7.11.30]
56963  RGMA; repulsive guidance molecule BMP co-receptor a [KO:K23096]
285704  RGMB; repulsive guidance molecule BMP co-receptor b [KO:K06847]
269  AMHR2; anti-Mullerian hormone receptor type 2 [KO:K04672] [EC:2.7.11.30]
7046  TGFBR1; transforming growth factor beta receptor 1 [KO:K04674] [EC:2.7.11.30]
7048  TGFBR2; transforming growth factor beta receptor 2 [KO:K04388] [EC:2.7.11.30]
91  ACVR1B; activin A receptor type 1B [KO:K13567] [EC:2.7.11.30]
93  ACVR2B; activin A receptor type 2B [KO:K13596] [EC:2.7.11.30]
130399  ACVR1C; activin A receptor type 1C [KO:K13568] [EC:2.7.11.30]
25805  BAMBI; BMP and activin membrane bound inhibitor [KO:K10162]
4086  SMAD1; SMAD family member 1 [KO:K04676]
4090  SMAD5; SMAD family member 5 [KO:K16790]
4093  SMAD9; SMAD family member 9 [KO:K16791]
4087  SMAD2; SMAD family member 2 [KO:K04500]
4088  SMAD3; SMAD family member 3 [KO:K23605]
4089  SMAD4; SMAD family member 4 [KO:K04501]
4091  SMAD6; SMAD family member 6 [KO:K04677]
4092  SMAD7; SMAD family member 7 [KO:K19631]
57154  SMURF1; SMAD specific E3 ubiquitin protein ligase 1 [KO:K04678] [EC:2.3.2.26]
64750  SMURF2; SMAD specific E3 ubiquitin protein ligase 2 [KO:K04678] [EC:2.3.2.26]
9372  ZFYVE9; zinc finger FYVE-type containing 9 [KO:K04679]
9765  ZFYVE16; zinc finger FYVE-type containing 16 [KO:K04679]
57817  HAMP; hepcidin antimicrobial peptide [KO:K23106]
3397  ID1; inhibitor of DNA binding 1, HLH protein [KO:K04680]
3398  ID2; inhibitor of DNA binding 2 [KO:K17693]
3399  ID3; inhibitor of DNA binding 3, HLH protein [KO:K17694]
3400  ID4; inhibitor of DNA binding 4, HLH protein [KO:K17695]
5933  RBL1; RB transcriptional corepressor like 1 [KO:K04681]
1874  E2F4; E2F transcription factor 4 [KO:K04682]
1875  E2F5; E2F transcription factor 5 [KO:K04682]
7027  TFDP1; transcription factor Dp-1 [KO:K04683]
1387  CREBBP; CREB binding protein [KO:K04498] [EC:2.3.1.48]
2033  EP300; E1A binding protein p300 [KO:K04498] [EC:2.3.1.48]
6667  SP1; Sp1 transcription factor [KO:K04684]
7050  TGIF1; TGFB induced factor homeobox 1 [KO:K19383]
60436  TGIF2; TGFB induced factor homeobox 2 [KO:K19553]
4609  MYC; MYC proto-oncogene, bHLH transcription factor [KO:K04377]
1030  CDKN2B; cyclin dependent kinase inhibitor 2B [KO:K04685]
5308  PITX2; paired like homeodomain 2 [KO:K04686]
9978  RBX1; ring-box 1 [KO:K03868] [EC:2.3.2.32]
8454  CUL1; cullin 1 [KO:K03347]
6500  SKP1; S-phase kinase associated protein 1 [KO:K03094]
5594  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
5595  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
3458  IFNG; interferon gamma [KO:K04687]
7124  TNF; tumor necrosis factor [KO:K03156]
387  RHOA; ras homolog family member A [KO:K04513]
6093  ROCK1; Rho associated coiled-coil containing protein kinase 1 [KO:K04514] [EC:2.7.11.1]
5519  PPP2R1B; protein phosphatase 2 scaffold subunit Abeta [KO:K03456]
5518  PPP2R1A; protein phosphatase 2 scaffold subunit Aalpha [KO:K03456]
5515  PPP2CA; protein phosphatase 2 catalytic subunit alpha [KO:K04382] [EC:3.1.3.16]
5516  PPP2CB; protein phosphatase 2 catalytic subunit beta [KO:K04382] [EC:3.1.3.16]
6198  RPS6KB1; ribosomal protein S6 kinase B1 [KO:K04688] [EC:2.7.11.1]
6199  RPS6KB2; ribosomal protein S6 kinase B2 [KO:K04688] [EC:2.7.11.1]
Reference
  Authors
Shi Y, Massague J.
  Title
Mechanisms of TGF-beta signaling from cell membrane to the nucleus.
  Journal
Cell 113:685-700 (2003)
DOI:10.1016/S0092-8674(03)00432-X
Reference
  Authors
Derynck R, Zhang YE.
  Title
Smad-dependent and Smad-independent pathways in TGF-beta family signalling.
  Journal
Nature 425:577-84 (2003)
DOI:10.1038/nature02006
Reference
  Authors
Massague J.
  Title
How cells read TGF-beta signals.
  Journal
Nat Rev Mol Cell Biol 1:169-78 (2000)
DOI:10.1038/35043051
Reference
  Authors
Siegel PM, Massague J.
  Title
Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer.
  Journal
Nat Rev Cancer 3:807-21 (2003)
DOI:10.1038/nrc1208
Reference
  Authors
Shimasaki S, Moore RK, Otsuka F, Erickson GF.
  Title
The bone morphogenetic protein system in mammalian reproduction.
  Journal
Endocr Rev 25:72-101 (2004)
DOI:10.1210/er.2003-0007
Reference
  Authors
De Robertis EM, Larrain J, Oelgeschlager M, Wessely O.
  Title
The establishment of Spemann's organizer and patterning of the vertebrate embryo.
  Journal
Nat Rev Genet 1:171-81 (2000)
DOI:10.1038/35042039
Reference
  Authors
Gumienny TL, Padgett RW.
  Title
The other side of TGF-beta superfamily signal regulation: thinking outside the cell.
  Journal
Trends Endocrinol Metab 13:295-9 (2002)
DOI:10.1016/S1043-2760(02)00615-X
Reference
  Authors
Hamada H, Meno C, Watanabe D, Saijoh Y.
  Title
Establishment of vertebrate left-right asymmetry.
  Journal
Nat Rev Genet 3:103-13 (2002)
DOI:10.1038/nrg732
Reference
  Authors
Chang H, Brown CW, Matzuk MM.
  Title
Genetic analysis of the mammalian transforming growth factor-beta superfamily.
  Journal
Endocr Rev 23:787-823 (2002)
DOI:10.1210/er.2002-0003
Reference
  Authors
Morita K, Chow KL, Ueno N.
  Title
Regulation of body length and male tail ray pattern formation of Caenorhabditis elegans by a member of TGF-beta family.
  Journal
Development 126:1337-47 (1999)
Reference
PMID:9847239
  Authors
Krishna S, Maduzia LL, Padgett RW.
  Title
Specificity of TGFbeta signaling is conferred by distinct type I receptors and their associated SMAD proteins in Caenorhabditis elegans.
  Journal
Development 126:251-60 (1999)
Reference
  Authors
Chen Y, Mironova E, Whitaker LL, Edwards L, Yost HJ, Ramsdell AF.
  Title
ALK4 functions as a receptor for multiple TGF beta-related ligands to regulate left-right axis determination and mesoderm induction in Xenopus.
  Journal
Dev Biol 268:280-94 (2004)
DOI:10.1016/j.ydbio.2003.12.035
Reference
  Authors
Onichtchouk D, Chen YG, Dosch R, Gawantka V, Delius H, Massague J, Niehrs C
  Title
Silencing of TGF-beta signalling by the pseudoreceptor BAMBI.
  Journal
Nature 401:480-5 (1999)
DOI:10.1038/46794
Reference
  Authors
Yan X, Lin Z, Chen F, Zhao X, Chen H, Ning Y, Chen YG
  Title
Human BAMBI cooperates with Smad7 to inhibit transforming growth factor-beta signaling.
  Journal
J Biol Chem 284:30097-104 (2009)
DOI:10.1074/jbc.M109.049304
Reference
PMID:8093006
  Authors
Hildebrand A, Romaris M, Rasmussen LM, Heinegard D, Twardzik DR, Border WA, Ruoslahti E
  Title
Interaction of the small interstitial proteoglycans biglycan, decorin and fibromodulin with transforming growth factor beta.
  Journal
Biochem J 302 ( Pt 2):527-34 (1994)
DOI:10.1042/bj3020527
Reference
  Authors
Soo C, Hu FY, Zhang X, Wang Y, Beanes SR, Lorenz HP, Hedrick MH, Mackool RJ, Plaas A, Kim SJ, Longaker MT, Freymiller E, Ting K
  Title
Differential expression of fibromodulin, a transforming growth factor-beta modulator, in fetal skin development and scarless repair.
  Journal
Am J Pathol 157:423-33 (2000)
DOI:10.1016/s0002-9440(10)64555-5
Reference
  Authors
Anderson GJ, Frazer DM
  Title
Iron metabolism meets signal transduction.
  Journal
Nat Genet 38:503-4 (2006)
DOI:10.1038/ng0506-503
Reference
  Authors
Canali S, Core AB, Zumbrennen-Bullough KB, Merkulova M, Wang CY, Schneyer AL, Pietrangelo A, Babitt JL
  Title
Activin B Induces Noncanonical SMAD1/5/8 Signaling via BMP Type I Receptors in Hepatocytes: Evidence for a Role in Hepcidin Induction by Inflammation in Male Mice.
  Journal
Endocrinology 157:1146-62 (2016)
DOI:10.1210/en.2015-1747
Reference
  Authors
Ganz T, Nemeth E
  Title
Iron homeostasis in host defence and inflammation.
  Journal
Nat Rev Immunol 15:500-10 (2015)
DOI:10.1038/nri3863
Reference
  Authors
Babitt JL, Zhang Y, Samad TA, Xia Y, Tang J, Campagna JA, Schneyer AL, Woolf CJ, Lin HY
  Title
Repulsive guidance molecule (RGMa), a DRAGON homologue, is a bone morphogenetic protein co-receptor.
  Journal
J Biol Chem 280:29820-7 (2005)
DOI:10.1074/jbc.M503511200
Reference
  Authors
Samad TA, Rebbapragada A, Bell E, Zhang Y, Sidis Y, Jeong SJ, Campagna JA, Perusini S, Fabrizio DA, Schneyer AL, Lin HY, Brivanlou AH, Attisano L, Woolf CJ
  Title
DRAGON, a bone morphogenetic protein co-receptor.
  Journal
J Biol Chem 280:14122-9 (2005)
DOI:10.1074/jbc.M410034200
Related
pathway
hsa04010  MAPK signaling pathway
hsa04110  Cell cycle
hsa04120  Ubiquitin mediated proteolysis
hsa04210  Apoptosis
KO pathway
ko04350   

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