PTPN11 and cancer: Specifically, the cancer-associated SHP2 mutants reduce the concentration of p-IRS-1 required to stimulate the phosphatase activity of SHP2 by one to two orders of magnitude (the p-IRS-1 AC50 value for stimulation), except in the case of the most active mutant SHP2E76K, which is essentially fully activated in the absence of p-IRS-1 and thus insensitive to further stimulation (Fig. 3d).