| A couple of years ago we have discovered a novel target for cAMP, the Rap1 guanine nucleotide exchange factor Epac (De Rooij et al., 1998). This discovery was important since the dogma was that all major cAMP effects are mediated by protein kinase A (PKA). Since cAMP is a mediator of many processes we embarked on two aspects of this novel cAMP-pathway. First we studied the molecular mechanism by which cAMP activates Epac and Rap1 and secondly we studied the function of this pathway. The first studies revealed a very intriguing interplay between cAMP and Epac. Mutational and crystallographic studies revealed a possible mechanism as to how cAMP induces a conformational change which underlies the mechanism of activation (Rehmann et al., 2003). Most likely, this mechanism is universal and also accounts for PKA. In addition, using rational drug design we have synthesized a novel cAMP analog that is specific for Epac and which can be used for functional studies (Enserink et al., 2002). The functional studies revealed that this novel cAMP pathway is involved in the control of integrin-mediated cell adhesion (Rangarajan et al., 2003) and very recently we established a role of this pathway in the regulation of insulin secretion (Kang et al., 2003). It is predicted that Epac will be involved in many more processes in which cAMP plays a crucial role. |
