KEGG   PATHWAY: hsa04350Help
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
BRITE hierarchy
Pathway map
hsa04350  TGF-beta signaling pathway

Ortholog table
hsa_M00679  BMP signaling [PATH:hsa04350]
hsa_M00680  TGF-beta signaling [PATH:hsa04350]
hsa_M00681  Activin signaling [PATH:hsa04350]
N00063  TGF-beta signaling pathway
H00409  Type 2 diabetes mellitus
H00430  Fibrodysplasia ossificans progressiva
H00431  Ossification of the posterior longitudinal ligament of spine
H00434  Camurati-Engelmann disease
H00466  Grebe dysplasia
H00467  Fibular hypoplasia and complex brachydactyly
H00468  Acromesomelic dysplasia, Demirhan type
H00482  Brachydactyly
H00483  Angel shaped phalangoepiphyseal dysplasia
H00484  Multiple synostosis syndrome
H00533  Hereditary hemorrhagic telangiectasia
H00554  Bicuspid aortic valve
H00609  Persistent Mullerian duct syndrome
H00620  Axenfeld-Rieger syndrome
H00632  Heterotaxy
H00778  Tarsal-carpal coalition syndrome
H00800  Loeys-Dietz syndrome
H00801  Familial thoracic aortic aneurysm and dissection
H00852  Klippel-Feil syndrome
H00868  Stapes ankylosis with broad thumb and toes
H00958  Congenital stromal corneal dystrophy
H01023  Juvenile polyposis syndrome
H01024  Hereditary mixed polyposis syndrome
H01075  Peters anomaly
H01149  Ring dermoid of cornea
H01385  Rienhoff syndrome
H01619  Primary pulmonary hypertension
H01621  Pulmonary arterial hypertension
H02102  Myhre syndrome
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)
Other DBs
BSID: 83064
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  MINOS1-NBL1; MINOS1-NBL1 readthrough [KO:K19558]
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]
653  BMP5; bone morphogenetic protein 5 [KO:K04663]
654  BMP6; bone morphogenetic protein 6 [KO:K16620]
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]
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]
3625  INHBB; inhibin subunit beta B [KO:K22687]
3626  INHBC; inhibin subunit beta C [KO:K22688]
83729  INHBE; inhibin subunit beta E [KO:K22689]
4838  NODAL; nodal growth differentiation factor [KO:K04666]
659  BMPR2; bone morphogenetic protein receptor type 2 [KO:K04671] [EC:]
269  AMHR2; anti-Mullerian hormone receptor type 2 [KO:K04672] [EC:]
7048  TGFBR2; transforming growth factor beta receptor 2 [KO:K04388] [EC:]
92  ACVR2A; activin A receptor type 2A [KO:K04670] [EC:]
93  ACVR2B; activin A receptor type 2B [KO:K13596] [EC:]
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:]
7046  TGFBR1; transforming growth factor beta receptor 1 [KO:K04674] [EC:]
91  ACVR1B; activin A receptor type 1B [KO:K13567] [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:K04500]
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]
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)
KO pathway

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