Phase Separation of Disease-Associated SHP2 Mutants Underlies MAPK Hyperactivation.
Phase Separation of Disease-Associated SHP2 Mutants Underlies MAPK Hyperactivation.
复制标题
疾病相关 SHP2 突变体的相分离是 MAPK 过度激活的基础。
DOI：
10.1016/j.cell.2020.09.002
复制
发表时间：
2020-10-15
期刊：
影响因子：
64.5
通讯作者：
Zhu J
中科院分区：
文献类型：
--
作者：
Zhu G;Xie J;Kong W;Xie J;Li Y;Du L;Zheng Q;Sun L;Guan M;Li H;Zhu T;He H;Liu Z;Xia X;Kan C;Tao Y;Shen HC;Li D;Wang S;Yu Y;Yu ZH;Zhang ZY;Liu C;Zhu J
由PTPN11编码的非受体蛋白酪氨酸磷酸酶（PTP） SHP2在正常发育过程中对RAS-MAPK信号传导起重要作用。为什么PTPN11的酶激活和灭活突变会导致具有重叠临床表现的人类发育障碍，这一直令人困惑。在这里，我们发现了这些疾病相关的SHP2突变体共有的一种常见的液-液相分离（LLPS）行为。SHP2 LLPS由保守的折叠良好的PTP结构域通过多价静电相互作用介导，并通过构象变化受到内在自抑制机制的调节。SHP2变构抑制剂可以减弱SHP2突变体的LLPS，从而增强SHP2 PTP活性。此外，疾病相关的SHP2突变体可以在LLPS中招募和激活WT SHP2，从而促进MAPK的激活。这些结果不仅表明LLPS在shp2相关人类疾病的发病机制中发挥了功能获得机制的作用，也为PTP可能受LLPS调控提供了证据，并可作为治疗靶点。RAS-MAPK通路中一种关键磷酸酶的疾病相关突变体通过显性功能获得机制进行相分离，这解释了酶激活和酶失活突变如何调节该通路并成为治疗靶点。
The non-receptor protein tyrosine phosphatase (PTP) SHP2, encoded by PTPN11, plays an essential role in RAS-MAPK signaling during normal development. It has been perplexing as why both enzymatically activating and inactivating mutations in PTPN11 result in human developmental disorders with overlapping clinical manifestations. Here, we uncover a common liquid-liquid phase separation (LLPS) behavior shared by these disease-associated SHP2 mutants. SHP2 LLPS is mediated by the conserved well-folded PTP domain through multivalent electrostatic interactions and regulated by an intrinsic autoinhibitory mechanism through conformational changes. SHP2 allosteric inhibitors can attenuate LLPS of SHP2 mutants, which boosts SHP2 PTP activity. Moreover, disease-associated SHP2 mutants can recruit and activate WT SHP2 in LLPS to promote MAPK activation. These results not only suggest that LLPS serves as a gain-of-function mechanism involved in the pathogenesis of SHP2-associated human diseases, but also provide evidences that PTP may be regulated by LLPS that can be therapeutically targeted. Disease-associated mutants of a critical phosphatase in the RAS-MAPK pathway undergo phase separation through a dominant gain-of-function mechanism, explaining how both enzymatically activating and -inactivating mutations dysregulate the pathway and can be therapeutically targeted.
登录
查看更多内容
影响因子：
2
作者：
Merks, JHM;Caron, HN;Hennekam, RCM
通讯作者：
Hennekam, RCM
影响因子：
56.9
作者：
Franzmann, Titus M.;Jahnel, Marcus;Alberti, Simon
通讯作者：
Alberti, Simon
影响因子：
8
作者：
Miyamoto, D.;Miyamoto, M.;Hatakeyama, M.
通讯作者：
Hatakeyama, M.
影响因子：
64.8
作者：
Li, Pilong;Banjade, Sudeep;Cheng, Hui-Chun;Kim, Soyeon;Chen, Baoyu;Guo, Liang;Llaguno, Marc;Hollingsworth, Javoris V.;King, David S.;Banani, Salman F.;Russo, Paul S.;Jiang, Qiu-Xing;Nixon, B. Tracy;Rosen, Michael K.
通讯作者：
Rosen, Michael K.
影响因子：
1.2
作者：
Laux, Daniela;Kratz, Christian;Sauerbrey, Axel
通讯作者：
Sauerbrey, Axel