G alpha 12 and G alpha 13 regulate extracellular signal-regulated kinase and c-Jun kinase pathways by different mechanisms in COS-7 cells

Many growth factors and agonists for G protein-coupled receptors activate mitogen-activated protein (MAP) kinase pathways, including the extracellular signal-regulated kinase (ERK) pathway and the c-Jun kinase (JNK) pathway. Transient transfection of dominant negative and constitutively active pathway components in COS-7 cells shows that two G protein subunits, G alpha 12 and G alpha 13, inhibit the ERK pathway and stimulate the JNK pathway. Constitutively active (GTPase-deficient) G alpha 12 and G alpha 13 both inhibit ERK pathway activation by epidermal growth factor. A G alpha 13/alpha z chimera, which responds to stimulation by G(i)-coupled receptors, mediates inhibition of ERK via such a receptor, the dopamine-2 receptor. In addition, expression of a dominant negative mutant of the GTPase, Cdc42, blocks activation of the JNK pathway by G alpha 12 and G alpha 13 but does not alter inhibition of ERK activation by the same G alpha proteins; conversely, mutationally activated Cdc42 stimulates the JNK pathway but has no effect on the ERK pathway, Our results show that different mechanisms mediate two effects of G alpha 12 and G alpha 13: the ERK pathway inhibition is mediated at the level of MAP kinase kinase in a Ras- and Raf-independent fashion, whereas the JNK pathway stimulation is mediated by Cdc42.