癌症中SMAD4 MH2结构域突变
中文名称
通路描述
SMAD4的MH2结构域是癌症中最常突变的SMAD4区域。MH2结构域的突变导致SMAD4功能丧失，通过阻止SMAD4与TGFβ受体复合物激活的R-SMADs（SMAD2和SMAD3）形成具有转录活性的异三聚体来实现。热点MH2结构域氨基酸残基包括D351、P356和R361。这三个热点残基映射到SMAD2和SMAD3中保守的L1环，该环参与介导SMAD异三聚体和同源三聚体的形成。SMAD4 MH2结构域中其他常突变残基包括A406、K428和R515，其中R515位于L3环，对于与SMAD2和SMAD3磷酸化基序（Ser-Ser-X-Ser）的结合至关重要。
英文描述
SMAD4 MH2 Domain Mutants in Cancer 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).
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).
所含基因
2 个基因