Hyperactivation of p21(ras) and the hematopoietic-specific Rho GTPase Rac2, cooperate to alter the proliferation of neurofibromin-deficient mast cells in vivo and in vitro

Mutations in the NF1 tumor suppressor gene cause neurofibromatosis type I ( NF1), a disease characterized by the formation of cutaneous neurofibromas i nfiltrated with a high density of degranulating mast cells. A hallmark of c ell lines generated from NF1 patients of Nf1-deficient mice is their propen sity to hyperproliferate. Neurofibromin, the protein encoded by NF1, negati vely regulates p21(ras) activity by accelerating the conversion of Ras-GTP to Ras-GDP. However, identification of alterations in specific P21(ras) eff ector pathways that control proliferation in NF1-deficient cells is incompl ete and critical for understanding disease pathogenesis. Recent studies hav e suggested that the proliferative effects of p21(ras) may depend on signal ing outputs from small Rho GTPases, Rac and Rho, but the physiologic import ance of these interactions in an animal disease model has not been establis hed. Using a genetic intercross between Nf1(+/-) and Rac2(-/-) mice, we now provide genetic evidence to support a biochemical model where hyperactivat ion of the extracellular signal-regulated kinase (ERK) via the hematopoieti c-specific Rho GTPase, Rac2, directly contributes to the hyperproliferation of Nf1-deficient mast cells in vitro and in vivo. Further, we demonstrate that Rac2 functions as mediator of cross-talk between phosphoinositide 3-ki nase (PI-3K) and the classical p21(ras)-Raf-Mek-ERK pathway to confer a dis tinct proliferative advantage to Nf1(+/-) mast cells. Thus, these studies i dentify Rac2 as a novel mediator of cross-talk between PI-3K and the p21(ra s)-ERK pathway which function to alter the cellular phenotype of a cell lin eage involved in the pathologic complications of a common genetic disease.