RAS-DEPENDENT SIGNALING BY THE GTPASE-DEFICIENT MUTANT OF G-ALPHA(12)

G alpha(12) and G alpha(13) regulate diverse responses through the sma ll GTPases Ras, CDC42, Rac, and Rho, Whereas they activate similar res ponses in many different cell types, they also activate more specific and critical signaling pathways in other cell types, In COS cells, in which both G alpha(12) and G alpha(13) stimulate Na+/H+ exchange, they do so by activating different signaling pathways, Here we report that the differential recruitment of specific small GTPases by G alpha(12) and G alpha(13) defines the molecular basis for their functional diff erences. We have observed that the stimulation of Na+/H+ exchange by t he GTPase-deficient mutant of G alpha(12) (G alpha(12)QL) requires a f unctional Ras and is independent of Rac/CDC42 and Jun kinase signaling module. By contrast, the stimulation of Na+/H+ exchange by G alpha(13 )QL requires a functional Rac/CDC42 CDC42 and the Jun kinase signaling module, Our results also indicate that G alpha(12)QL-Ras stimulation of Na+/H+ exchange involves a D609-sensitive phospholipase and protein kinase C, These studies, for the first time, describe a novel G alpha (12)-specific signaling pathway involving Has, phosphatidylcholine hyd rolysis, and protein kinase C in the regulation of Na+/H+ exchange.