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

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

K14736

transferrin

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

K04687

interferon gamma

K03156

tumor necrosis factor superfamily, member 2

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

K04673

bone morphogenetic protein receptor type-1A [EC:2.7.11.30]

K13578

bone morphogenetic protein receptor type-1B [EC:2.7.11.30]

K04675

activin receptor type-1 [EC:2.7.11.30]

K04671

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

K04670

activin receptor type-2A [EC:2.7.11.30]

K23100

hemojuvelin

K06766

neogenin

K26535

hereditary hemochromatosis protein

K23910

transferrin receptor protein 2

K06503

transferrin receptor

K23096

repulsive guidance molecule A

K06847

RGM domain family member B

K04672

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

K04674

TGF-beta receptor type-1 [EC:2.7.11.30]

K04388

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

K26257

epithelial membrane protein 3

K26316

transforming growth factor beta activator LRRC32

K26317

transforming growth factor beta activator LRRC33

K13567

activin receptor type-1B [EC:2.7.11.30]

K13596

activin receptor type-2B [EC:2.7.11.30]

K13568

activin receptor type-1C [EC:2.7.11.30]

K26168

immunoglobulin superfamily member 1

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:2.3.2.26]

K04679

MAD, mothers against decapentaplegic interacting protein

K03868

E3 ubiquitin-protein ligase RBX1 [EC:2.3.2.32]

K03347

cullin 1

K03094

S-phase kinase-associated protein 1

K04371

mitogen-activated protein kinase 1/3 [EC:2.7.11.24]

K04513

Ras homolog gene family, member A

K04514

Rho-associated protein kinase 1 [EC:2.7.11.1]

K03456

serine/threonine-protein phosphatase 2A regulatory subunit A

K04382

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

K04688

ribosomal protein S6 kinase beta [EC:2.7.11.1]

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:2.3.1.48]

K04684

transcription factor Sp1

K18499

Ski-like protein

K26503

Ski oncogene

K11644

paired amphipathic helix protein Sin3a

K06067

histone deacetylase 1/2 [EC:3.5.1.98]

K04650

nuclear receptor co-repressor 1

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

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