中国科学院上海有机化学研究所朱继东和刘聪研究组合作取得最新进展。他们发现疾病相关SHP2突变体的相分离是RAS促分裂原激活的蛋白激酶（MAPK）超活化的基础。2020年9月30日出版的《细胞》杂志发表了这项成果。
他们发现了与这些疾病相关的SHP2突变体共有的常见液相-液相分离（LLPS）行为。 SHP2 LLPS通过多价静电相互作用由保守的折叠良好的非受体蛋白酪氨酸磷酸酶（PTP）结构域介导，并通过构象变化由固有的自抑制机制调节。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，与疾病相关的SHP2突变体可以募集并激活LLPS中的野生型（WT）SHP2，从而促进MAPK激活。这些结果不仅表明LLPS是参与和SHP2相关的人类疾病的发病机理的功能获得机制，而且还提供了PTP可能受到可治疗靶向的LLPS调节的证据。
据悉，在正常发育过程中，PTPN11编码的PTP SHP2在MAPK信号传导中起重要作用。关于为什么PTPN11中的酶促激活和失活突变都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。
附：英文原文
Title: Phase Separation of Disease-Associated SHP2 Mutants Underlies MAPK Hyperactivation
Author: Guangya Zhu, Jingjing Xie, Wenna Kong, Jingfei Xie, Yichen Li, Lin Du, Qiangang Zheng, Lin Sun, Mingfeng Guan, Huan Li, Tianxin Zhu, Hao He, Zhenying Liu, Xi Xia, Chen Kan, Youqi Tao, Hong C. Shen, Dan Li, Siying Wang, Yongguo Yu, Zhi-Hong Yu, Zhong-Yin Zhang, Cong Liu, Jidong Zhu
Issue&Volume: 2020-09-30
Abstract: The non-receptor protein tyrosine phosphatase (PTP) SHP2, encoded by PTPN11, plays an essential role in RAS-mitogen-activated protein kinase (MAPK) signalingduring normal development. It has been perplexing as to why both enzymatically activatingand 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 bythese disease-associated SHP2 mutants. SHP2 LLPS is mediated by the conserved well-foldedPTP domain through multivalent electrostatic interactions and regulated by an intrinsicautoinhibitory mechanism through conformational changes. SHP2 allosteric inhibitorscan attenuate LLPS of SHP2 mutants, which boosts SHP2 PTP activity. Moreover, disease-associatedSHP2 mutants can recruit and activate wild-type (WT) SHP2 in LLPS to promote MAPKactivation. These results not only suggest that LLPS serves as a gain-of-functionmechanism involved in the pathogenesis of SHP2-associated human diseases but alsoprovide evidence that PTP may be regulated by LLPS that can be therapeutically targeted.
DOI: 10.1016/j.cell.2020.09.002
Source: https://www.cell.com/cell/fulltext/S0092-8674(20)31143-0