ACTIVATION OF JUN KINASE STRESS-ACTIVATED PROTEIN-KINASE BY GTPASE-DEFICIENT MUTANTS OF G-ALPHA(12) AND G-ALPHA(13)

Signal transduction pathways regulated by G(12) and G(13) heterotrimer ic G proteins are largely unknown, Expression of activated, GTPase-def icient mutants of alpha(12) and alpha(12) alter physiological response s such as Na+/H+ exchanger activity, but the effector pathways control ling these responses have not been defined, We have found that the exp ression of GTPase-deficient mutants of alpha(12) (alpha(12)Q229L) or a lpha(13) (alpha(13)Q226L) leads to robust activation of the Jun kinase /stress-activated protein kinase (JNK/SAPK) pathway. Inducible alpha(1 2)Q226L and alpha(13)Q226L expression vectors stably transfected in NI H 3T3 cells demonstrated JNK/SAPK activation but not extracellular res ponse/mitogen-activated protein kinase activation, Transient transfect ion of alpha(12)Q229L and alpha(13)Q226L also activated the JNK/SAPK p athway in COS-1 cells, Expression of the GTPase-deficient mutant of al pha(q) (alpha(q)Q209L) but not alpha(i) (alpha(i)Q205L) or alpha(s) (a lpha(s)Q227L) was also able to activate the JNK/SAPK pathway, Function al Ras signaling was required for alpha(12)Q229L and alpha(13)Q226L ac tivation of the JNK/SAPK pathway; expression of competitive inhibitory N(17)Ras inhibited JNK/SAPK activation in response to both alpha(12)Q 229L and alpha(13)Q226L. The results describe for the first time a Ras -dependent signal transduction pathway involving JNK/SAPK regulated by alpha(12) and alpha(13).