SHP2 is a phosphatase involved in key signaling pathways, and mutations in its encoding gene PTPN11 are linked to cancers—including juvenile hematologic malignancies—and developmental disorders such as Noonan syndrome. SHP2 comprises two SH2 phosphotyrosine (pY) recognition domains (N-SH2 and C-SH2) and a catalytic phosphatase domain (PTP). Binding of phosphorylated partners to its SH2 domains triggers a conformational shift that activates the protein and enhances dephosphorylation activity. However, pY-binding peptides (PPs) can also be dephosphorylated, and SHP2’s allosteric mechanism may underlie feedback regulation. Yet, a key discrepancy remains: the peptide concentration needed to fully activate SHP2 versus that required to saturate the N-SH2 domain varies by over two orders of magnitude depending on the sequence. This may suggest that peptides are dephosphorylated, perhaps with different efficacy. To explore the role of dephosphorylation, we use our patented non-dephosphorylatable peptide (NDP) designed for oncogenic therapy and NDP analogs of natural binders pY1172 and pY546. By comparing activation profiles and binding affinities—via catalytic and fluorescence anisotropy assays—of PPs/NDPs analogs, we propose a strategy to decouple these mechanisms and better understand SHP2 feedback regulation.
Strofaldi et al. (Sun,) studied this question.