Classic Ras and R‐Ras function in neurofibromatosis type 1‐associated malignant peripheral nerve sheath tumors

Abstract

Neurofibromin negatively regulates classic Ras (H, N, and K‐Ras) and R‐Ras (R‐Ras, R‐Ras2, and M‐Ras) proteins. Neurofibromin loss in malignant peripheral nerve sheath tumors (MPNSTs) thus leads to Ras hyperactivation, suggesting that the Ras proteins required for MPNST pathogenesis would be appropriate therapeutic targets. To identify the classic Ras and/or R‐Ras proteins mediating MPNST proliferation and migration, we examined the expression and action of these molecules in MPNST cells. H‐Ras, N‐Ras, K‐Ras, and R‐Ras2 were uniformly present in 8 MPNST cell lines, while R‐Ras and M‐Ras expression was variable. MPNST cells also expressed specific guanine nucleotide exchange factors capable of activating classic Ras and R‐Ras proteins. We found that R‐Ras2 was constitutively active in MPNST cells and that K‐Ras was activated in these cells by neuregulin‐1, a growth factor that promotes MPNST proliferation and migration. Dominant negative mutants of H‐Ras, an inhibitor of classic Ras proteins, and R‐Ras, which inhibits the R‐Ras subfamily, both inhibited MPNST mitogenesis. We conclude that both classic Ras and R‐Ras subfamily members likely contribute to MPNST pathogenesis. We are currently identifying the specific Ras proteins required for MPNST proliferation and migration by ablating their expression with lentiviruses that express tetracycline‐regulated shRNAs. Supported by R01 NS048353.