Reactome | Phosphorylated SMAD2 and SMAD3 form a complex with SMAD4

Phosphorylated SMAD2 and SMAD3 form a complex with SMAD4

Stable Identifier

R-HSA-170847

Type

Reaction [transition]

Species

Homo sapiens

Compartment

cytosol

ReviewStatus

5/5

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Phosphorylated SMAD2 and SMAD3 form a complex with SMAD4

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The phosphorylated C-terminal tail of R-SMAD induces a conformational change in the MH2 domain (Qin et al. 2001, Chacko et al. 2004), which now acquires high affinity towards Co-SMAD i.e. SMAD4 (common mediator of signal transduction in TGF-beta/BMP signaling). The R-SMAD:Co-SMAD complex (Nakao et al. 1997) most likely is a trimer of two R-SMADs with one Co-SMAD (Kawabata et al. 1998). It is important to note that the Co-SMAD itself cannot be phosphorylated as it lacks the C-terminal serine motif.

ZFYVE16 (endofin) promotes SMAD heterotrimer formation. ZFYVE16 can bind TGFBR1 and facilitate SMAD2 phosphorylation, and it can also bind SMAD4, but the exact mechanism of ZFYVE16 (endofin) action in the context of TGF-beta receptor signaling is not known (Chen et al. 2007).

SARS-CoV-1 nucleocapsid protein (N) associates with SMAD3 and this binding interferes with the complex formation between SMAD3 and SMAD4. By this mechanism N modulates TGF-beta signaling to block apoptosis of SARS-CoV-infected host cells (Zhao et al. 2008).

Literature References

PubMed ID	Title	Journal	Year
9311995	TGF-beta receptor-mediated signalling through Smad2, Smad3 and Smad4 Nakao, A, Souchelnytskyi, S, Kawabata, M, Ishisaki, A, Oeda, E, Tamaki, K, Hanai, J, Heldin, CH, Miyazono, K, ten Dijke, P	EMBO J	1997
11779503	Crystal structure of a phosphorylated Smad2. Recognition of phosphoserine by the MH2 domain and insights on Smad function in TGF-beta signaling. Wu, JW, Hu, M, Chai, J, Seoane, J, Huse, M, Li, C, Rigotti, DJ, Kyin, S, Muir, TW, Fairman, R, Massague, J, Shi, Y	Mol Cell	2001
15350224	Structural basis of heteromeric smad protein assembly in TGF-beta signaling Chacko, BM, Qin, BY, Tiwari, A, Shi, G, Lam, S, Hayward, LJ, De Caestecker, M, Lin, K	Mol Cell	2004
17272273	Endofin, a FYVE domain protein, interacts with Smad4 and facilitates transforming growth factor-beta signaling Chen, YG, Wang, Z, Ma, J, Zhang, L, Lu, Z	J. Biol. Chem.	2007
9670020	Smad proteins exist as monomers in vivo and undergo homo- and hetero-oligomerization upon activation by serine/threonine kinase receptors Kawabata, M, Inoue, H, Hanyu, A, Imamura, T, Miyazono, K	EMBO J	1998
11779505	Structural basis of Smad1 activation by receptor kinase phosphorylation Qin, BY, Chacko, BM, Lam, SS, de Caestecker, MP, Correia, JJ, Lin, K	Mol Cell	2001