Deep mutational scanning of the multi-domain phosphatase SHP2 reveals mechanisms of regulation and pathogenicity.

ABSTRACT: Multi-domain signaling enzymes are often regulated through extensive inter-domain interactions, and disruption of inter-domain interfaces by mutations can lead to aberrant signaling and diseases. For example, the tyrosine phosphatase SHP2 contains two phosphotyrosine recognition domains that auto-inhibit its catalytic domain. SHP2 is canonically activated by binding of these non-catalytic domains to phosphoproteins, which destabilizes its auto-inhibited state, and several mutations at the main auto-inhibitory interface have been shown to hyperactivate SHP2 in cancers and developmental disorders. Hundreds of clinically observed mutations in SHP2 have not been characterized, but their locations suggest alternative modes of dysregulation. Here, we perform deep mutational scanning on full-leng

SUBMITTER: Jiang Z 

PROVIDER: S-EPMC12216643 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature