KEGG PATHWAY: ko04350

PATHWAY: ko04350

Entry

ko04350                     Pathway

Name

TGF-beta signaling pathway

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

ko04350

TGF-beta signaling pathway

Other DBs

GO:

0007179

Orthology

K03094

SKP1, CBF3D; S-phase kinase-associated protein 1

K03156

TNF, TNFA; tumor necrosis factor superfamily, member 2

K03347

CUL1, CDC53; cullin 1

K03456

PPP2R1; serine/threonine-protein phosphatase 2A regulatory subunit A

K03868

RBX1, ROC1; E3 ubiquitin-protein ligase RBX1 [EC:2.3.2.32]

K04371

ERK, MAPK1_3; mitogen-activated protein kinase 1/3 [EC:2.7.11.24]

K04377

MYC; Myc proto-oncogene protein

K04382

PPP2C; serine/threonine-protein phosphatase 2A catalytic subunit [EC:3.1.3.16]

K04388

TGFBR2; TGF-beta receptor type-2 [EC:2.7.11.30]

K04498

EP300, CREBBP, KAT3; E1A/CREB-binding protein [EC:2.3.1.48]

K04500

SMAD2; mothers against decapentaplegic homolog 2

K04501

SMAD4; mothers against decapentaplegic homolog 4

K04513

RHOA; Ras homolog gene family, member A

K04514

ROCK1; Rho-associated protein kinase 1 [EC:2.7.11.39]

K04650

NCOR1, N-CoR; nuclear receptor co-repressor 1

K04657

CHRD; chordin

K04658

NOG; noggin

K04660

DCN; decorin

K04661

FST; follistatin

K04662

BMP4; bone morphogenetic protein 4

K04663

BMP5; bone morphogenetic protein 5

K04664

GDF5; growth differentiation factor 5

K04665

AMH; anti-mullerian hormone

K04666

NODAL; nodal

K04667

INHBA; inhibin beta A chain

K04668

LEFTY; left-right determination factor

K04670

ACVR2A; activin receptor type-2A [EC:2.7.11.30]

K04671

BMPR2; bone morphogenetic protein receptor type-2 [EC:2.7.11.30]

K04672

AMHR2; anti-mullerian hormone receptor type-2 [EC:2.7.11.30]

K04673

BMPR1A, ALK3, CD292; bone morphogenetic protein receptor type-1A [EC:2.7.11.30]

K04674

TGFBR1, ALK5; TGF-beta receptor type-1 [EC:2.7.11.30]

K04675

ACVR1, ALK2; activin receptor type-1 [EC:2.7.11.30]

K04676

SMAD1; mothers against decapentaplegic homolog 1

K04677

SMAD6; mothers against decapentaplegic homolog 6

K04678

SMURF; E3 ubiquitin ligase SMURF1/2 [EC:2.3.2.26]

K04679

MADHIP, SARA; MAD, mothers against decapentaplegic interacting protein

K04680

ID1; DNA-binding protein inhibitor ID1

K04681

RBL1; retinoblastoma-like protein 1

K04682

E2F4_5; transcription factor E2F4/5

K04683

TFDP1; transcription factor Dp-1

K04684

SP1; transcription factor Sp1

K04685

CDKN2B, P15, INK4B; cyclin-dependent kinase inhibitor 2B

K04686

PITX2; paired-like homeodomain transcription factor 2

K04687

IFNG; interferon gamma

K04688

RPS6KB; ribosomal protein S6 kinase beta [EC:2.7.11.1]

K06067

HDAC1_2; histone deacetylase 1/2 [EC:3.5.1.98]

K06503

TFRC, CD71; transferrin receptor

K06766

NEO1; neogenin

K06825

FBN1; fibrillin 1

K06847

RGMB; RGM domain family member B

K08121

FMOD; fibromodulin

K10162

BAMBI; BMP and activin membrane-bound inhibitor

K11644

SIN3A; paired amphipathic helix protein Sin3a

K13375

TGFB1; transforming growth factor beta-1

K13376

TGFB2; transforming growth factor beta-2

K13377

TGFB3; transforming growth factor beta-3

K13567

ACVR1B, ALK4; activin receptor type-1B [EC:2.7.11.30]

K13568

ACVR1C, ALK7; activin receptor type-1C [EC:2.7.11.30]

K13578

BMPR1B, ALK6, CDw293; bone morphogenetic protein receptor type-1B [EC:2.7.11.30]

K13596

ACVR2B; activin receptor type-2B [EC:2.7.11.30]

K14736

TF; transferrin

K16620

BMP6; bone morphogenetic protein 6

K16621

BMP7; bone morphogenetic protein 7

K16622

BMP8; bone morphogenetic protein 8

K16790

SMAD5; mothers against decapentaplegic homolog 5

K16791

SMAD9, SMAD8; mothers against decapentaplegic homolog 9

K16857

THBS1; thrombospondin 1

K17693

ID2; DNA-binding protein inhibitor ID2

K17694

ID3; DNA-binding protein inhibitor ID3

K17695

ID4; DNA-binding protein inhibitor ID4

K17696

EMC; DNA-binding protein inhibitor ID, other

K18499

SKIL; Ski-like protein

K19383

TGIF1; homeobox protein TGIF1

K19553

TGIF2; homeobox protein TGIF2

K19558

NBL1; neuroblastoma suppressor of tumorigenicity 1

K19559

LTBP1; latent transforming growth factor beta binding protein 1

K19631

SMAD7; mothers against decapentaplegic homolog 7

K20012

GDF6; growth differentiation factor 6

K20013

GDF7; growth differentiation factor 7

K21283

BMP2; bone morphogenetic protein 2

K22687

INHBB; inhibin beta B chain

K22688

INHBC; inhibin beta C chain

K22689

INHBE; inhibin beta E chain

K23096

RGMA; repulsive guidance molecule A

K23100

HJV, RGMC; hemojuvelin

K23106

HAMP; hepcidin

K23318

GREM; gremlin

K23377

THSD4, ADAMTSL6; thrombospondin type-1 domain-containing protein 4

K23605

SMAD3; mothers against decapentaplegic homolog 3

K23910

TFR2; transferrin receptor protein 2

K26168

IGSF1; immunoglobulin superfamily member 1

K26257

EMP3; epithelial membrane protein 3

K26316

LRRC32; transforming growth factor beta activator LRRC32

K26317

NRROS, LRRC33; transforming growth factor beta activator LRRC33

K26503

SKI; Ski oncogene

K26535

HFE; hereditary hemochromatosis protein

Compound

C14819

Fe3+

Reference

PMID:12809600

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

PMID:14534577

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

PMID:11252892

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

PMID:14557817

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

PMID:14769828

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

PMID:11252746

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

PMID:12163231

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

PMID:11836504

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

PMID:12466190

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

PMID:10021351

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

PMID:15063168

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

PMID:10519551

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

PMID:19758997

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

PMID:10934147

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

PMID:16642010

Authors

Anderson GJ, Frazer DM

Title

Iron metabolism meets signal transduction.

Journal

Nat Genet 38:503-4 (2006)
DOI:10.1038/ng0506-503

Reference

PMID:26735394

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

PMID:26160612

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

PMID:15975920

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

PMID:15671031

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

Reference

PMID:33925597

Authors

Vogt AS, Arsiwala T, Mohsen M, Vogel M, Manolova V, Bachmann MF

Title

On Iron Metabolism and Its Regulation.

Journal

Int J Mol Sci 22:ijms22094591 (2021)
DOI:10.3390/ijms22094591