The small GTPase Rap1 in cAMP signalling

Abstract

Cyclic AMP was the first identified second messenger. A large number of studies have elucidated the fundamental role of cAMP in the wide range of cellular responses to many hormones and neurotransmitters. Cyclic AMP activates three different signal transduction pathways: the protein kinase A (PKA) pathway, the cyclic nucleotide-gated ion channel pathway, and the Epac signalling pathway. Epac is an exchange factor for the small GTPases Rap1 and Rap2. Rap GTPases are closely related to the small GTPase Ras, and when it was found that Rap1 could trap Raf1 in an inactive complex, and that overexpression of an activated Rap1 mutant could interfere with ERK signalling in fibroblasts, it was hypothesized that Rap1 antagonizes Ras by trapping Ras effectors in an inactive complex through its highly homologous effector domain. In contrast, Rap1 has also been suggested to activate Ras effectors and induce cellular transformation of Swiss 3T3 fibroblasts. More recently, Rap1 has been implicated in integrin-dependent cell adhesion and migration. In this study we developed a novel cAMP analogue, which specifically activates Epac but not PKA. Using this analogue, we subsequently show that endogenous Rap1 is unlikely to play a role in ERK signalling. Rather, Rap1 is likely to have a signalling function independent of Ras. Indeed, we show a function of the cAMP-Epac-Rap1 signaling pathway in regulation of integrin-mediated cell adhesion, and possibly also in regulation of p70 S6 kinase