Reactome | SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription

SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription

Stable Identifier

R-HSA-2173796

Type

Pathway

Species

Homo sapiens

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SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription

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After phosphorylated SMAD2 and/or SMAD3 form a heterotrimer with SMAD4, SMAD2/3:SMAD4 complex translocates to the nucleus (Xu et al. 2000, Kurisaki et al. 2001, Xiao et al. 2003). In the nucleus, linker regions of SMAD2 and SMAD3 within SMAD2/3:SMAD4 complex can be phosphorylated by CDK8 associated with cyclin C (CDK8:CCNC) or CDK9 associated with cyclin T (CDK9:CCNT). CDK8/CDK9-mediated phosphorylation of SMAD2/3 enhances transcriptional activity of SMAD2/3:SMAD4 complex, but also primes it for ubiquitination and consequent degradation (Alarcon et al. 2009).

The transfer of SMAD2/3:SMAD4 complex to the nucleus can be assisted by other proteins, such as WWTR1. In human embryonic cells, WWTR1 (TAZ) binds SMAD2/3:SMAD4 heterotrimer and mediates TGF-beta-dependent nuclear accumulation of SMAD2/3:SMAD4. The complex of WWTR1 and SMAD2/3:SMAD4 binds promoters of SMAD7 and SERPINE1 (PAI-1 i.e. plasminogen activator inhibitor 1) genes and stimulates their transcription (Varelas et al. 2008). Stimulation of SMAD7 transcription by SMAD2/3:SMAD4 represents a negative feedback loop in TGF-beta receptor signaling. SMAD7 can be downregulated by RNF111 ubiquitin ligase (Arkadia), which binds and ubiquitinates SMAD7, targeting it for degradation (Koinuma et al. 2003).

SMAD2/3:SMAD4 heterotrimer also binds the complex of RBL1 (p107), E2F4/5 and TFDP1/2 (DP1/2). The resulting complex binds MYC promoter and inhibits MYC transcription. Inhibition of MYC transcription contributes to anti-proliferative effect of TGF-beta (Chen et al. 2002). SMAD2/3:SMAD4 heterotrimer also associates with transcription factor SP1. SMAD2/3:SMAD4:SP1 complex stimulates transcription of a CDK inhibitor CDKN2B (p15-INK4B), also contributing to the anti-proliferative effect of TGF-beta (Feng et al. 2000).

MEN1 (menin), a transcription factor tumor suppressor mutated in a familial cancer syndrome multiple endocrine neoplasia type 1, forms a complex with SMAD2/3:SMAD4 heterotrimer, but transcriptional targets of SMAD2/3:SMAD4:MEN1 have not been elucidated (Kaji et al. 2001, Sowa et al. 2004, Canaff et al. 2012).

JUNB is also an established transcriptional target of SMAD2/3:SMAD4 complex (Wong et al. 1999).

Literature References

PubMed ID	Title	Journal	Year
18568018	TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal Wrana, JL, Peerani, R, Rao, BM, Samavarchi-Tehrani, P, Sakuma, R, Zandstra, PW, Varelas, X, Yaffe, MB, Dembowy, J	Nat Cell Biol	2008
14657019	Arkadia amplifies TGF-beta superfamily signalling through degradation of Smad7 Miyazono, K, Goto, K, Shinozaki, M, Imamura, T, Nukiwa, T, Komuro, A, Ebina, M, Miyazawa, K, Saitoh, M, Hanyu, A, Koinuma, D	EMBO J	2003
11274402	Inactivation of menin, a Smad3-interacting protein, blocks transforming growth factor type beta signaling Kaji, H, Lebrun, JJ, Canaff, L, Goltzman, D, Hendy, GN	Proc Natl Acad Sci U S A	2001
11294908	Transforming growth factor-beta induces nuclear import of Smad3 in an importin-beta1 and Ran-dependent manner Yoneda, Y, Moustakas, A, Heldin, CH, Kose, S, Kurisaki, A	Mol Biol Cell	2001
22275377	Impaired Transforming Growth Factor-? (TGF-?) Transcriptional Activity and Cell Proliferation Control of a Menin In-frame Deletion Mutant Associated with Multiple Endocrine Neoplasia Type 1 (MEN1) Kaji, H, Vanbellinghen, JF, Canaff, L, Goltzman, D, Hendy, GN	J Biol Chem	2012
15150273	Menin is required for bone morphogenetic protein 2- and transforming growth factor beta-regulated osteoblastic differentiation through interaction with Smads and Runx2 Kaji, H, Sowa, H, Komori, T, Canaff, L, Chihara, K, Sugimoto, T, Hendy, GN	J Biol Chem	2004
10022869	Smad3-Smad4 and AP-1 complexes synergize in transcriptional activation of the c-Jun promoter by transforming growth factor beta Wong, C, Wang, XF, Datto, MB, Rougier-Chapman, EM, Li, JM, Liberati, NT, Frederick, JP	Mol Cell Biol	1999
12592392	An extended bipartite nuclear localization signal in Smad4 is required for its nuclear import and transcriptional activity Lodish, HF, Latek, R, Xiao, Z	Oncogene	2003
10934479	The nuclear import function of Smad2 is masked by SARA and unmasked by TGFbeta-dependent phosphorylation Massague, J, Xu, L, Chen, YG	Nat Cell Biol	2000
19914168	Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-beta pathways Xi, Q, Zaromytidou, AI, Pan, D, Miller, AN, Macias, MJ, Barlas, A, Manova-Todorova, K, Yu, J, Massague, J, Gao, S, Sapkota, G, Alarcon, C, Fujisawa, S	Cell	2009
12150994	E2F4/5 and p107 as Smad cofactors linking the TGFbeta receptor to c-myc repression Massague, J, Siegel, PM, Chen, CR, Kang, Y	Cell	2002
11013220	Smad2, Smad3 and Smad4 cooperate with Sp1 to induce p15(Ink4B) transcription in response to TGF-beta Lin, X, Feng, XH, Derynck, R	EMBO J	2000