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) heterotrimeric G proteins are largely unknown, Expression of activated, GTPase-deficient mutants of alpha(12) and alpha(12) alter physiological responses such as Na+/H+ exchanger activity, but the effector pathways controlling these responses have not been defined, We have found that the expression of GTPase-deficient mutants of alpha(12) (alpha(12)Q229L) or alpha(13) (alpha(13)Q226L) leads to robust activation of the Jun kinase/stress-activated protein kinase (JNK/SAPK) pathway. Inducible alpha(12)Q226L and alpha(13)Q226L expression vectors stably transfected in NIH 3T3 cells demonstrated JNK/SAPK activation but not extracellular response/mitogen-activated protein kinase activation, Transient transfection of alpha(12)Q229L and alpha(13)Q226L also activated the JNK/SAPK pathway in COS-1 cells, Expression of the GTPase-deficient mutant of alpha(q) (alpha(q)Q209L) but not alpha(i) (alpha(i)Q205L) or alpha(s) (alpha(s)Q227L) was also able to activate the JNK/SAPK pathway, Functional Ras signaling was required for alpha(12)Q229L and alpha(13)Q226L activation of the JNK/SAPK pathway; expression of competitive inhibitory N(17)Ras inhibited JNK/SAPK activation in response to both alpha(12)Q229L 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).