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
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Rattus norvegicus (rat) [GN:rno]

PMID:12809600

Shi Y, Massague J.

Mechanisms of TGF-beta signaling from cell membrane to the nucleus.

Cell 113:685-700 (2003)
DOI:10.1016/S0092-8674(03)00432-X

PMID:14534577

Derynck R, Zhang YE.

Smad-dependent and Smad-independent pathways in TGF-beta family signalling.

Nature 425:577-84 (2003)
DOI:10.1038/nature02006

PMID:11252892

Massague J.

How cells read TGF-beta signals.

Nat Rev Mol Cell Biol 1:169-78 (2000)
DOI:10.1038/35043051

PMID:14557817

Siegel PM, Massague J.

Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer.

Nat Rev Cancer 3:807-21 (2003)
DOI:10.1038/nrc1208

PMID:14769828

Shimasaki S, Moore RK, Otsuka F, Erickson GF.

The bone morphogenetic protein system in mammalian reproduction.

Endocr Rev 25:72-101 (2004)
DOI:10.1210/er.2003-0007

PMID:11252746

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)
DOI:10.1038/35042039

PMID:12163231

Gumienny TL, Padgett RW.

The other side of TGF-beta superfamily signal regulation: thinking outside the cell.

Trends Endocrinol Metab 13:295-9 (2002)
DOI:10.1016/S1043-2760(02)00615-X

PMID:11836504

Hamada H, Meno C, Watanabe D, Saijoh Y.

Establishment of vertebrate left-right asymmetry.

Nat Rev Genet 3:103-13 (2002)
DOI:10.1038/nrg732

PMID:12466190

Chang H, Brown CW, Matzuk MM.

Genetic analysis of the mammalian transforming growth factor-beta superfamily.

Endocr Rev 23:787-823 (2002)
DOI:10.1210/er.2002-0003

PMID:10021351

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)

PMID:9847239

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)

PMID:15063168

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)
DOI:10.1016/j.ydbio.2003.12.035

PMID:10519551

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)
DOI:10.1038/46794

PMID:19758997

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)
DOI:10.1074/jbc.M109.049304

PMID:8093006

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)
DOI:10.1042/bj3020527

PMID:10934147

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)
DOI:10.1016/s0002-9440(10)64555-5

PMID:16642010

Anderson GJ, Frazer DM

Iron metabolism meets signal transduction.

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

PMID:26735394

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)
DOI:10.1210/en.2015-1747

PMID:26160612

Ganz T, Nemeth E

Iron homeostasis in host defence and inflammation.

Nat Rev Immunol 15:500-10 (2015)
DOI:10.1038/nri3863

PMID:15975920

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)
DOI:10.1074/jbc.M503511200

PMID:15671031

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)
DOI:10.1074/jbc.M410034200