Mutation of (Encoding SHP-2) Promotes MEK Activation and Malignant Progression in Neurofibromin-Deficient Cells in a Manner Sensitive to Mutation.

Germline mutations of cause neurofibromatosis type 1 () through the activation of the signaling pathway, and some patients develop malignant peripheral nerve sheath tumors (MPNSTs). Here, we established subclones of the human -MPNST cell line sNF96.2 that manifest increased tumorigenic activity and increased phosphorylation of the protein kinases MEK and Akt relative to the parental cells. Genomic DNA sequencing identified 14 additional heterozygous mutations within the coding regions of 13 cancer- and other disease-related genes in these subclones. One of these genes, , encodes SHP-2, and the forced expression of the identified G503V mutant of SHP-2 increased both tumorigenic activity and MEK phosphorylation in parental sNF96.2 cells, suggesting that the combination of and mutations induces the pathological activation of the pathway. These effects of SHP-2 (G503V) were inhibited by the coexpression of the G370A mutant of , which was also detected in the highly malignant subclones, and this inhibition was accompanied by the calpain-dependent cleavage of SHP-2 (G503V). The cleavage of SHP-2 (G503V) and suppression of MEK phosphorylation mediated by (G370A) were not detected in -intact (HeLa) cells. Tumor promotion by SHP-2 (G503V) and its suppression by (G370A) may serve as a basis for the development of new treatment strategies for .