Normal p21^N-ras couples bombesin and other growth factor receptors to inositol phosphate production

Abstract

Many receptors, in response to ligand activation, trigger inositol phospholipid breakdown, which leads to rapid intracellular responses^1–4. The sustained activation of this pathway is believed to be at least one of the factors involved in the stimulation of cell growth and there has been much speculation^4–6 that certain oncogenes use this pathway to effect uncontrolled cellular proliferation. It has been suggested⁷, by analogy with the receptor-mediated control of adenylate cyclase⁸, that the receptor stimulation of inositol phospholipid metabolism is mediated through a guanine nucleotide regulatory protein (G-protein) called G_p (or N_p). Although such a species has not been identified, there is now strong experimental evidence that this process is mediated by a G-protein distinct from the stimulatory and inhibitory G-proteins (G_s and G_i, respectively)^9–12. The ras genes code for a plasma membrane protein, p21, whose only known biochemical property is a high-affinity GTPase activity¹³. We show here that the expression of normal p21^N–ras in NIH 3T3 fibroblasts leads to the coupling of certain growth factor receptors to stimulated inositol phosphate production. We propose that the N-ras proto-oncogene encodes a protein which couples the receptors for certain growth factors to the stimulation of phospholipase C. Thus, N-ras p 21 may be the putative G_p or a functionally related protein.