RAS-DEPENDENT ACTIVATION OF FIBROBLAST MITOGEN-ACTIVATED PROTEIN-KINASE BY 5-HT1A RECEPTOR VIA A G-PROTEIN BETA-GAMMA-SUBUNIT-INITIATED PATHWAY

Serotonin (5-HT) is a potent mitogen in many cells types, an action wh ich is frequently mediated through pertussis toxin-sensitive G protein s. In the current study, we used pharmacological inhibitors and domina nt negative signaling constructs to delineate elements which participa te in the activation of MAPK, a growth-associated mitogen-activated pr otein kinase, by human G protein-coupled 5-HT1A receptor transfected i nto CHO-K1 cells in a stable manner, The activation pathway does not d irectly involve phorbol ester-sensitive protein kinase C types, but do es require (i) pertussis toxin-sensitive G protein beta gamma-subunits , (ii) a staurosporine- and genistein-sensitive protein kinase, (iii) phosphoinositide-3'-kinase activity, (iv) activation of Sos in a multi molecular complex that contains p46(Shc) and p52(Shc), and Grb2, (v) t he GTPase p21(Ras), and (vi) the protein kinase p74(Raf-1). These data demonstrate that the 5-HT1A receptor mediates MAPK activity by conver gence upon a common activation pathway that is shared with receptor ty rosine kinases.