Phase Separation of Disease-Associated SHP2 Mutants Underlies MAPK Hyperactivation

Cell. 2020 Oct 15;183(2):490-502.e18. doi: 10.1016/j.cell.2020.09.002. Epub 2020 Sep 30.


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.

Keywords: MAPK activation; Noonan syndrome; Noonan syndrome with multiple lentigines; PTPN11; SHP2; allosteric inhibitor; conformation change; disease-associated mutants; electrostatic interactions; liquid-liquid phase separation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Animals
  • Child
  • Child, Preschool
  • Female
  • Gain of Function Mutation / genetics
  • HEK293 Cells
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • MAP Kinase Signaling System / physiology
  • Male
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism*
  • Mouse Embryonic Stem Cells
  • Mutation / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism*
  • Signal Transduction
  • src Homology Domains / genetics


  • Mitogen-Activated Protein Kinases
  • PTPN11 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11