Proximity-labeling proteomics reveals remodeled interactomes and altered localization of pathogenic SHP2 variants

ABSTRACT: Missense mutations in PTPN11, which encodes the protein tyrosine phosphatase SHP2, are common in several developmental disorders and cancers. While many mutations disrupt auto-inhibition and hyperactivate SHP2, several do not enhance catalytic activity. Both activating and non-activating mutations could potentially drive pathogenic signaling by altering SHP2 interactions or localization. We employed proximity-labeling proteomics to map the interaction networks of wild-type SHP2, ten clinically-relevant mutants, and SHP2 bound to an inhibitor that stabilizes its auto-inhibited state. Our analyses reveal mutation- and inhibitor-dependent alterations in the SHP2 interactome, with several mutations also changing localization. Some mutants show increased mitochondrial localization and impact mi

SUBMITTER: Anne, Elise van Vlimmeren 

PROVIDER: S-SCDT-10_1038-S44319-025-00674-4 | biostudies-other |

REPOSITORIES: biostudies-other