Cyclic AMP-Mediated Inhibition of Cell Growth Requires the Small G Protein Rap1

Abstract

In many normal and transformed cell types, the intracellular second messenger cyclic AMP (cAMP) blocks the effects of growth factors and serum on mitogenesis, proliferation, and cell cycle progression. cAMP exerts these growth-inhibitory effects via inhibition of the mitogen-activated protein (MAP) kinase cascade. Here, using Hek293 and NIH 3T3 cells, we show that cAMP's inhibition 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-1 and limits Ras-dependent activation of ERK. In NIH 3T3 cells, Rap1 is required not only for cAMP's inhibition of ERK activation but for inhibition of cell proliferation and mitogenesis as well.

ACKNOWLEDGMENTS

We thank Kendall Carey (Vollum Institute, Oregon Health Sciences University) for scientific discussions and experimental assistance and Johannes Bos (University of Utrecht) for providing valuable reagents. We thank Kendall Carey, Tara Dillon, and Hong Yao (Vollum Institute, Oregon Health Sciences University) for critical reading of the manuscript and sharing technical and scientific expertise.

This work was supported by the NCI (P.J.S.S.).