KEGG   PATHWAY: hsa04350
hsa04350                    Pathway                                
TGF-beta signaling pathway - Homo sapiens (human)
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.
Environmental Information Processing; Signal transduction
Pathway map
hsa04350  TGF-beta signaling pathway

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
N00063  TGF-beta signaling pathway
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
Homo sapiens (human) [GN:hsa]
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:]
658  BMPR1B; bone morphogenetic protein receptor type 1B [KO:K13578] [EC:]
90  ACVR1; activin A receptor type 1 [KO:K04675] [EC:]
659  BMPR2; bone morphogenetic protein receptor type 2 [KO:K04671] [EC:]
92  ACVR2A; activin A receptor type 2A [KO:K04670] [EC:]
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:]
7046  TGFBR1; transforming growth factor beta receptor 1 [KO:K04674] [EC:]
7048  TGFBR2; transforming growth factor beta receptor 2 [KO:K04388] [EC:]
91  ACVR1B; activin A receptor type 1B [KO:K13567] [EC:]
93  ACVR2B; activin A receptor type 2B [KO:K13596] [EC:]
130399  ACVR1C; activin A receptor type 1C [KO:K13568] [EC:]
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:]
64750  SMURF2; SMAD specific E3 ubiquitin protein ligase 2 [KO:K04678] [EC:]
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:]
2033  EP300; E1A binding protein p300 [KO:K04498] [EC:]
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:]
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:]
5595  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:]
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:]
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:]
5516  PPP2CB; protein phosphatase 2 catalytic subunit beta [KO:K04382] [EC:]
6198  RPS6KB1; ribosomal protein S6 kinase B1 [KO:K04688] [EC:]
6199  RPS6KB2; ribosomal protein S6 kinase B2 [KO:K04688] [EC:]
Shi Y, Massague J.
Mechanisms of TGF-beta signaling from cell membrane to the nucleus.
Cell 113:685-700 (2003)
Derynck R, Zhang YE.
Smad-dependent and Smad-independent pathways in TGF-beta family signalling.
Nature 425:577-84 (2003)
Massague J.
How cells read TGF-beta signals.
Nat Rev Mol Cell Biol 1:169-78 (2000)
Siegel PM, Massague J.
Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer.
Nat Rev Cancer 3:807-21 (2003)
Shimasaki S, Moore RK, Otsuka F, Erickson GF.
The bone morphogenetic protein system in mammalian reproduction.
Endocr Rev 25:72-101 (2004)
De Robertis EM, Larrain J, Oelgeschlager M, Wessely O.
The establishment of Spemann's organizer and patterning of the vertebrate embryo.
Nat Rev Genet 1:171-81 (2000)
Gumienny TL, Padgett RW.
The other side of TGF-beta superfamily signal regulation: thinking outside the cell.
Trends Endocrinol Metab 13:295-9 (2002)
Hamada H, Meno C, Watanabe D, Saijoh Y.
Establishment of vertebrate left-right asymmetry.
Nat Rev Genet 3:103-13 (2002)
Chang H, Brown CW, Matzuk MM.
Genetic analysis of the mammalian transforming growth factor-beta superfamily.
Endocr Rev 23:787-823 (2002)
Morita K, Chow KL, Ueno N.
Regulation of body length and male tail ray pattern formation of Caenorhabditis elegans by a member of TGF-beta family.
Development 126:1337-47 (1999)
Krishna S, Maduzia LL, Padgett RW.
Specificity of TGFbeta signaling is conferred by distinct type I receptors and their associated SMAD proteins in Caenorhabditis elegans.
Development 126:251-60 (1999)
Chen Y, Mironova E, Whitaker LL, Edwards L, Yost HJ, Ramsdell AF.
ALK4 functions as a receptor for multiple TGF beta-related ligands to regulate left-right axis determination and mesoderm induction in Xenopus.
Dev Biol 268:280-94 (2004)
Onichtchouk D, Chen YG, Dosch R, Gawantka V, Delius H, Massague J, Niehrs C
Silencing of TGF-beta signalling by the pseudoreceptor BAMBI.
Nature 401:480-5 (1999)
Yan X, Lin Z, Chen F, Zhao X, Chen H, Ning Y, Chen YG
Human BAMBI cooperates with Smad7 to inhibit transforming growth factor-beta signaling.
J Biol Chem 284:30097-104 (2009)
Hildebrand A, Romaris M, Rasmussen LM, Heinegard D, Twardzik DR, Border WA, Ruoslahti E
Interaction of the small interstitial proteoglycans biglycan, decorin and fibromodulin with transforming growth factor beta.
Biochem J 302 ( Pt 2):527-34 (1994)
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
Differential expression of fibromodulin, a transforming growth factor-beta modulator, in fetal skin development and scarless repair.
Am J Pathol 157:423-33 (2000)
Anderson GJ, Frazer DM
Iron metabolism meets signal transduction.
Nat Genet 38:503-4 (2006)
Canali S, Core AB, Zumbrennen-Bullough KB, Merkulova M, Wang CY, Schneyer AL, Pietrangelo A, Babitt JL
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.
Endocrinology 157:1146-62 (2016)
Ganz T, Nemeth E
Iron homeostasis in host defence and inflammation.
Nat Rev Immunol 15:500-10 (2015)
Babitt JL, Zhang Y, Samad TA, Xia Y, Tang J, Campagna JA, Schneyer AL, Woolf CJ, Lin HY
Repulsive guidance molecule (RGMa), a DRAGON homologue, is a bone morphogenetic protein co-receptor.
J Biol Chem 280:29820-7 (2005)
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
DRAGON, a bone morphogenetic protein co-receptor.
J Biol Chem 280:14122-9 (2005)
hsa04010  MAPK signaling pathway
hsa04110  Cell cycle
hsa04120  Ubiquitin mediated proteolysis
hsa04210  Apoptosis
KO pathway

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