SMAD2/3 Phosphorylation Motif Mutants in Cancer

Stable Identifier
Homo sapiens
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The conserved phosphorylation motif Ser-Ser-X-Ser at the C-terminus of SMAD2 and SMAD3 is subject to disruptive mutations in cancer. The last two serine residues in this conserved motif, namely Ser465 and Ser467 in SMAD2 and Ser423 and Ser425 in SMAD3, are phosphorylated by the activated TGF beta receptor complex (Macias Silva et al. 1996, Nakao et al. 1997). Once phosphorylated, SMAD2 and SMAD3 form transcriptionally active heterotrimers with SMAD4 (Chacko et al. 2001, Chacko et al. 2004). Phosphorylation motif mutants of SMAD2 and SMAD3 cannot be activated by the TGF-beta receptor complex either because serine residues are substituted with amino acid residues that cannot be phosphorylated or because the phosphorylation motif is deleted from the protein sequence or truncated (Fleming et al. 2013).
Literature References
PubMed ID Title Journal Year
15350224 Structural basis of heteromeric smad protein assembly in TGF-beta signaling

Shi, G, De Caestecker, M, Lin, K, Chacko, BM, Hayward, LJ, Tiwari, A, Qin, BY, Lam, S

Mol Cell 2004
8980228 MADR2 is a substrate of the TGFbeta receptor and its phosphorylation is required for nuclear accumulation and signaling

Wrana, JL, Attisano, L, Abdollah, S, Hoodless, PA, Pirone, R, Macias-Silva, M

Cell 1996
11224571 The L3 loop and C-terminal phosphorylation jointly define Smad protein trimerization

Correia, JJ, Lam, SS, de Caestecker, MP, Qin, B, Chacko, BM, Lin, K

Nat. Struct. Biol. 2001
9346966 Phosphorylation of Ser465 and Ser467 in the C terminus of Smad2 mediates interaction with Smad4 and is required for transforming growth factor-beta signaling

Souchelnytskyi, S, Engstrom, U, ten Dijke, P, Heldin, CH, Wernstedt, C, Tamaki, K

J Biol Chem 1997
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
9311995 TGF-beta receptor-mediated signalling through Smad2, Smad3 and Smad4

Nakao, A, Miyazono, K, Souchelnytskyi, S, Ishisaki, A, Kawabata, M, ten Dijke, P, Heldin, CH, Oeda, E, Hanai, J, Tamaki, K

EMBO J 1997
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
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