2025 Theses Doctoral

Characterizing mechanisms of regulation and pathogenicity in SHP2 using deep mutational scanning

Jiang, Ziyuan

The protein tyrosine phosphatase SHP2 is a tightly regulated multi-domain signaling enzyme. Its two regulatory SH2 domains and catalytic phosphatase domain coordinate its catalytic activity and signaling capability through altering its domain arrangement, substrate interaction capacity and ligand binding specificity. Mutations of SHP2 have been found in cancers and developmental diseases. Some of the pathogenic SHP2 mutations have been thoroughly investigated, yielding valuable insights into SHP2 structure and regulation. However, hundreds of disease mutations of SHP2 remain poorly studied.

Characterization of more SHP2 mutations, especially disease mutations of potential functional importance, promises a deeper understanding of SHP2 structure, dynamics and signaling roles. Here, we comprehensively characterize the catalytic activity of all SHP2 single mutations with deep mutational scanning. With the activity profile, we further explore interesting mutations with biochemical, biophysical, cell biological assays and molecular dynamic simulations. These characterizations illustrate the roles of previously understudied SHP2 residues and mutations and further unveil key interactions and dynamic patterns regulating SHP2 catalysis, conformational change and signaling capacity.