RAS-DEPENDENT ACTIVATION OF MAP KINASE PATHWAY MEDIATED BY G-PROTEIN BETA-GAMMA-SUBUNITS

MITOGEN-ACTIVATED protein kinases, MAP kinases or ERKs (extracellular signal-regulated kinases) are rapidly stimulated by growth-promoting factors acting on a variety of cell-surface receptors (1,2). In turn, ERKs phosphorylate and regulate key intracellular enzymes and transcription factors involved in the control of cellular proliferation(3,4). The tyrosine-kinase class of growth-factor receptors transmits signals to ERKs in a multistep process that involves Ras and a limited number of defined molecules(5). In contrast, ERK activation by G-protein-coupled receptors is poorly understood(3,6), as is the role of ras in this signalling pathway(7,8). We have explored in COS-7 cells the mechanism of ERKs activation by m1 and m2 muscarinic receptors, typical examples of receptors coupled through Gq proteins to induce phosphatidylinositol hydrolysis and to G(i) proteins to inhibit adenylyl cyclase, respectively(9). Here we present evidence that ERK activation is mediated by beta gamma subunits of heterotrimeric G proteins acting on a ras-dependent pathway.