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Phase Separation of Disease-Associated SHP2 Mutants Underlies MAPK Hyperactivation.

Abstract：

:The non-receptor protein tyrosine phosphatase (PTP) SHP2, encoded by PTPN11, plays an essential role in RAS-mitogen-activated protein kinase (MAPK) signaling during normal development. It has been perplexing as to 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 wild-type (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 evidence that PTP may be regulated by LLPS that can be therapeutically targeted.

journal_name

Cell

journal_title

Cell

authors

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

doi

10.1016/j.cell.2020.09.002

subject

Has Abstract

pub_date

2020-10-15 00:00:00

pages

490-502.e18

issue

2

eissn

0092-8674

issn

1097-4172

pii

S0092-8674(20)31143-0

journal_volume

183

pub_type

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