SHP2 binds directly to SOS1 to enable RAS activation
Year: 2026
Type: preprint
Abstract: The protein-tyrosine phosphatase SHP2 ( PTPN11 ) regulates growth factor- and cytokine-induced RAS/ERK MAP kinase (MAPK) pathway activation, and aberrant SHP2 function causes developmental disorders and cancer 1–5 . It is widely believed that the catalytic activity of SHP2 is essential for pathway activation 1,4,6–8 . This view has shaped our interpretation of how germline PTPN11 mutations cause Noonan Syndrome (NS) and NS with Multiple Lentigines (NS-ML) 2,9 and how somatic mutations contribute to myeloproliferative neoplasms and solid tumors 1 . Here we identify a previously undetected, protein-tyrosine phosphatase (PTP) activity-independent mechanism that revises our understanding of how SHP2 promotes RAS/ERK activation. We find that certain mutations of the nucleophilic cysteine that abolish catalytic activity still promote RAS/ERK pathway activation in normal and neoplastic mammalian cells, zebrafish embryos, and mice. Structural studies show that the SHP2 PTP domain binds directly to the Son of Sevenless 1 (SOS1) Dbl homology (DH) domain. Proximity labeling and super-resolution microscopy demonstrate that SHP2/SOS1 interaction occurs in cells and facilitates SOS1 translocation to the plasma membrane to form clusters. Our results overturn decades of dogma on SHP2 regulation of the RAS/ERK pathway and provide new insights into the mechanism of action of disease-associated PTPN11 mutations.
Authors: Toshiyuki Araki, Yashika Agrawal, Sachin S. Katti, Hiep L.D. Nguyen, Daniel Pushparaju Yeggoni, Mitchell J. Geer, Wei Wei, Daniëlle T.J. Woutersen, Tieme Bijlsma, Cameron Genxuan Lian, Natalie M. Clark, Namrata D. Udeshi, Steven A. Carr, Heidi Stuhlmann, Michael A. Davies, Eli Rothenberg, Jeroen den Hertog, Rebecca Page, Benjamin G. Neel, Wolfgang Peti
Institutions: NYU Langone’s Laura and Isaac Perlmutter Cancer Center, New York University, UConn Health, University Medical Center Utrecht, Hubrecht Institute for Developmental Biology and Stem Cell Research, Broad Institute, Weill Cornell Medicine, The University of Texas MD Anderson Cancer Center, Leiden University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7164744806