PDZ-GEF1, a guanine nucleotide exchange factor specific for Rap1 and Rap2

The small GTPase Rap1 has been implicated in a variety of cellular processe s including the control of cell morphology, proliferation, and differentiat ion. Stimulation of a large variety of cell surface receptors results in th e rapid activation of Rap1, i.e. an increase in the GTP-bound form. This ac tivation is mediated by second messengers like calcium, cAMP, and diacylgly cerol, but additional pathways may exist as well. Here we describe a ubiqui tously expressed guanine nucleotide exchange factor of 200 kDa that activat es Rap1 both in vivo and in vitro. This exchange factor has two putative re gulatory domains: a domain with an amino acid sequence related to cAMP-bind ing domains and a PDZ domain. Therefore, we named it PDZ-GEF1. PDZ-GEFs are closely related to Epacs, Rap-specific exchange factors with a genuine cAM P binding site, that are directly regulated by cAMP. The domain related to cAMP-binding domains, like the cAMP binding site in Epac, serves as a negat ive regulatory domain. However, PDZ-GEF1 does not interact with cAMP or cGM P. Interestingly, PDZ-GEF1 also activates Rap2, a close relative of Rap1. T his is the first example of an exchange factor acting on Rap2. We conclude that PDZ-GEF1 is a guanine nucleotide exchange factor, specific for Rap1 an d Rap2, that is controlled by a negative regulatory domain.