Phosphorylated SMAD2/3 MH2 Domain Mutants do not bind SMAD4

Stable Identifier
Reaction [transition]
Homo sapiens
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Phosphorylated SMAD2 and SMAD3 MH2 domain mutants cannot form heterotrimers with SMAD4 (Fleming et al. 2013), leading to the loss of TGF-beta-induced regulation of gene expression and aberrant cell differentiation and proliferation.

SMAD2 MH2 domain mutants SMAD2 A354T, SMAD2 D300A, SMAD2 D300N and SMAD2 P305L, as well as SMAD3 MH2 domain mutants SMAD3 D258N and SMAD3 R268C are annotated as characterized mutant set members based on structural and/or functional studies (Fleming et al. 2013). SMAD2 mutants SMAD2 D300V and SMAD2 P305Q, and SMAD3 mutant SMAD2 R268C are annotated as candidate members of the mutant set, based on sequence similarity with characterized mutants.

As SMAD2 and SMAD3 MH2 domain mutations mainly affect amino acid residues involved in SMAD oligomerization (Fleming et al. 2013) and not residues involved in SMAD2/SMAD3 binding to ZFYVE9 (SARA) nor the phosphorylation motif (Wu et al. 2000), it is assumed that SARA can recruit SMAD2/3 MH2 domain mutants to activated TGF-beta receptor 1 (TGFBR1), and that SMAD2/3 MH2 domain mutants can be phosphorylated by TGFBR1, after which they would dissociate from TGFBR1, similarly to the wild-type SMAD2 and SMAD3. This has not been directly experimentally examined.

Literature References
PubMed ID Title Journal Year
23139211 SMAD2, SMAD3 and SMAD4 mutations in colorectal cancer

Mouradov, D, Jorissen, RN, Jones, IT, Tsui, C, Palmieri, M, Sieber, OM, Ward, RL, Fleming, NI, Mariadason, JM, Sakthianandeswaren, A, Lipton, L, Moore, J, Ruszkiewicz, AR, Busam, D, Christie, M, McLaughlin, S, Gibbs, P, Zhu, HJ, Strausberg, RL, Day, F, Li, S, Burgess, AW, Hawkins, NJ, Desai, J, Zhao, Q

Cancer Res. 2013
Normal reaction
Functional status

Loss of function of p-2S-SMAD2/3 MH2 Domain Mutants [cytosol]

Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
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