Cyclic AMP-mediated inhibition of cell growth requires the small G proteinRap1

In many normal and transformed cell types, the intracellular second messeng er cyclic AMP (cAMP) blocks the effects of growth factors and serum on mito genesis, proliferation, and cell cycle progression, cAMP exerts these growt h-inhibitory effects via inhibition of the mitogen-activated protein (MAP) kinase cascade. Here, using Hek293 and NIH 3T3 cells, we show that cAMP's i nhibition of the MAP kinase cascade is mediated by the small G protein Rap1 , Activation of Rap1 by cAMP induces the association of Rap1 with Raf-l and limits pas-dependent activation of ERK. In NIH 3T3 cells, Rap1 is required not only for cAMP's inhibition of ERK activation but for inhibition of cel l proliferation and mitogenesis as well.