PKA Phosphorylation of Src Mediates cAMP\u27s Inhibition of Cell Growth via Rap1

In fibrolast cells, cAMP antagonizes growth factor activation of ERKs and cell growth via PKA and the small P protein Rap1. We demonstrate here that PKA\u27s activation of Rap1 was mediated by the Rap1 guanine nucleotide exchange factor C3G, the adaptor Crk-L, the scaffold protein Cbl, and the tyrosine kinase Src. Src was required for cAMP activation of Rap1 and the inhibition of ERKs and cell growth. PKA activated Src both in vitro and in vivo by phosphorylation was required for cAMP\u27s activation of Src and Rap1, as well as cAMP\u27s inhibition of ERKs and cell proliferation. This study identifies an antiproliferative role for Src in the physiological regulation of cell growth by cAMP