KEGG   PATHWAY: ko04350
ko04350                     Pathway                                

TGF-beta signaling pathway
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
ko04350  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
H01149  Ring dermoid of cornea
H01385  Rienhoff syndrome
H01619  Primary pulmonary hypertension
H01621  Pulmonary arterial hypertension
H02102  Myhre syndrome
Other DBs
GO: 0007179
K04657  chordin
K04658  noggin
K19558  neuroblastoma suppressor of tumorigenicity 1
K23318  gremlin
K16857  thrombospondin 1
K04660  decorin
K08121  fibromodulin
K04668  left-right determination factor
K04661  follistatin
K21283  bone morphogenetic protein 2
K04662  bone morphogenetic protein 4
K16620  bone morphogenetic protein 6
K22687  inhibin beta B chain
K04663  bone morphogenetic protein 5
K16621  bone morphogenetic protein 7
K16622  bone morphogenetic protein 8
K04664  growth differentiation factor 5
K20012  growth differentiation factor 6
K20013  growth differentiation factor 7
K04665  anti-mullerian hormone
K23377  thrombospondin type-1 domain-containing protein 4
K06825  fibrillin 1
K19559  latent transforming growth factor beta binding protein 1
K13375  transforming growth factor beta-1
K13376  transforming growth factor beta-2
K13377  transforming growth factor beta-3
K04667  inhibin beta A chain
K22688  inhibin beta C chain
K22689  inhibin beta E chain
K04666  nodal
K06766  neogenin
K23100  hemojuvelin
K04673  bone morphogenetic protein receptor type-1A [EC:]
K13578  bone morphogenetic protein receptor type-1B [EC:]
K04675  activin receptor type-1 [EC:]
K04671  bone morphogenetic protein receptor type-2 [EC:]
K04670  activin receptor type-2A [EC:]
K23096  repulsive guidance molecule A
K06847  RGM domain family member B
K04672  anti-mullerian hormone receptor type-2 [EC:]
K04674  TGF-beta receptor type-1 [EC:]
K04388  TGF-beta receptor type-2 [EC:]
K13567  activin receptor type-1B [EC:]
K13596  activin receptor type-2B [EC:]
K13568  activin receptor type-1C [EC:]
K10162  BMP and activin membrane-bound inhibitor
K04676  mothers against decapentaplegic homolog 1
K16790  mothers against decapentaplegic homolog 5
K16791  mothers against decapentaplegic homolog 9
K04500  mothers against decapentaplegic homolog 2
K23605  mothers against decapentaplegic homolog 3
K04501  mothers against decapentaplegic homolog 4
K04677  mothers against decapentaplegic homolog 6
K19631  mothers against decapentaplegic homolog 7
K04678  E3 ubiquitin ligase SMURF1/2 [EC:]
K04679  MAD, mothers against decapentaplegic interacting protein
K23106  hepcidin
K04680  DNA-binding protein inhibitor ID1
K17693  DNA-binding protein inhibitor ID2
K17694  DNA-binding protein inhibitor ID3
K17695  DNA-binding protein inhibitor ID4
K17696  DNA-binding protein inhibitor ID, other
K04681  retinoblastoma-like protein 1
K04682  transcription factor E2F4/5
K04683  transcription factor Dp-1
K04498  E1A/CREB-binding protein [EC:]
K04684  transcription factor Sp1
K19383  homeobox protein TGIF1
K19553  homeobox protein TGIF2
K04377  Myc proto-oncogene protein
K04685  cyclin-dependent kinase inhibitor 2B
K04686  paired-like homeodomain transcription factor 2
K03868  RING-box protein 1 [EC:]
K03347  cullin 1
K03094  S-phase kinase-associated protein 1
K04371  mitogen-activated protein kinase 1/3 [EC:]
K04687  interferon gamma
K03156  tumor necrosis factor superfamily, member 2
K04513  Ras homolog gene family, member A
K04514  Rho-associated protein kinase 1 [EC:]
K03456  serine/threonine-protein phosphatase 2A regulatory subunit A
K04382  serine/threonine-protein phosphatase 2A catalytic subunit [EC:]
K04688  ribosomal protein S6 kinase beta [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)
ko04010  MAPK signaling pathway
ko04110  Cell cycle
ko04120  Ubiquitin mediated proteolysis
ko04210  Apoptosis

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