Mutations in PTPN11, which encodes SHP2, are linked to a spectrum of diseases, including Noonan syndrome, LEOPARD syndrome, and cancers like juvenile myelomonocytic leukemia.(1–3) SHP2 comprises a catalytic protein tyrosine phosphatase (PTP) domain, two regulatory SH2 (Src homology 2) domains (N-SH2 and C-SH2), and an unstructured C-terminal tail.(4, 5) Unperturbed, SHP2 exists in equilibrium between an active, open (10%), and an inactive, closed conformation (90%) in which the N-SH2 occludes the PTP active site (Fig. 1A).(6–8). This evidence concerns the gene PTPN11 and juvenile myelomonocytic leukemia.