IRS1 and cancer: To explore how SHP2 cancer mutations influence stimulation of the phosphatase by phospholigands, we titrated SHP2 variants with a synthetic bisphosphorylated peptide derived from IRS-1 (p-IRS-1), which stimulates phosphatase activity by engaging both the N-SH2 and C-SH2 domains, and quantified the effect on DiFMUP dephosphorylation as a function of added p-IRS-1 concentration (Fig. 3c).