Rac-dependent anti-apoptotic signaling by the insulin receptor cytoplasmicdomain

Mutations in the cytoplasmic domain of the insulin receptor that block the ability of the receptor to stimulate glucose uptake do not block the recept or's ability to inhibit apoptosis (Boehm, J. E., Chaika, O. V., and Lewis, R. E. (1998) J. Biol. Chem. 273, 7169-7176). To characterize this survival pathway we used a chimeric receptor (CSF1R/IR) consisting of the ligand-bin ding domain of the colony-stimulating factor-1 receptor spliced to the cyto plasmic domain of the insulin receptor and a mutated version of the chimeri c receptor containing a 12-amino acid deletion of the juxtamembrane domain (CSF1R/IR Delta 960). in addition to the inhibition of apoptosis, activatio n of either the CSF1R/IR or the CSF1R/IR Delta 960 rapidly induced membrane ruffling in Rat1 fibroblasts, The small GTPase Rac mediates membrane ruffl ing. Activated and dominant-inhibitory mutants of Rac and other small GTPas es were expressed in Rat1 fibroblasts to examine a potential link between t he intracellular pathways that induce membrane ruffling and promote cell su rvival. The anti-apoptotic action of the CSF1R/IR Delta 960 was reversed by dominant-inhibitory Rac(N17), but not by Ras(N17) or Cdc42(N17). Activated Rac(V12), but not Ras(D12) or Cdc2(V12), promoted cell survival in the abs ence of insulin. These data implicate Rac as a mediator of an unique anti-a poptotic signaling pathway activated by the insulin receptor cytoplasmic do main.