SMAD4 MH2 Domain Mutants in Cancer

Stable Identifier
Homo sapiens
Locations in the PathwayBrowser
SVG |   | PPTX  | SBGN
Click the image above or here to open this pathway in the Pathway Browser
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
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
9214508 A structural basis for mutational inactivation of the tumour suppressor Smad4

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

Nature 1997
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
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
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
Cite Us!