SMAD4 MH2 Domain Mutants in Cancer

Stable Identifier
R-HSA-3311021
Type
Pathway
Species
Homo sapiens
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The MH2 domain of SMAD4 is the most frequently mutated SMAD4 region in cancer. MH2 domain mutations result in the loss of function of SMAD4 by abrogating the formation of transcriptionally active heterotrimers of SMAD4 and TGF-beta receptor complex-activated R-SMADs - SMAD2 and SMAD3 (Shi et al. 1997, Chacko et al. 2001, Chacko et al. 2004, Fleming et al. 2013).

The hotspot MH2 domain amino acid residues that are targeted by missense mutations are Asp351 (D351), Pro356 (P356) and Arg361 (R361). These three hotspot residues map to the L1 loop which is conserved in SMAD2 and SMAD3 and is involved in intermolecular interactions that contribute to the formation of SMAD heterotrimers and homotrimers (Shi et al. 1997, Fleming et al. 2013). Other frequently mutated residues in the MH2 domain of SMAD4 - Ala406 (A406), Lys428 (K428) and Arg515 (R515) - are involved in binding the phosphorylation motif (Ser-Ser-X-Ser) of SMAD2 and SMAD3, with Arg515 in the L3 loop being critical for this interaction (Chacko et al. 2001, Chacko et al. 2004, Fleming et al. 2013).

Literature References
PubMed ID Title Journal Year
9214508 A structural basis for mutational inactivation of the tumour suppressor Smad4

Shi, Y, Hata, A, Lo, RS, Massagué, J, Pavletich, NP

Nature 1997
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
11224571 The L3 loop and C-terminal phosphorylation jointly define Smad protein trimerization

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

Nat. Struct. Biol. 2001
23139211 SMAD2, SMAD3 and SMAD4 mutations in colorectal cancer

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

Cancer Res. 2013
Participants
Participant Of
Disease
Name Identifier Synonyms
cancer 162 malignant tumor, malignant neoplasm, primary cancer
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