title: PDZ-GEF1, a guanine nucleotide exchange factor specific for Rap1 and Rap2.
abstract: The small GTPase Rap1 has been implicated in a variety of cellular processes including the control of cell morphology, proliferation, and differentiation. Stimulation of a large variety of cell surface receptors results in the rapid activation of Rap1, i.e. an increase in the GTP-bound form. This activation is mediated by second messengers like calcium, cAMP, and diacylglycerol, but additional pathways may exist as well. Here we describe a ubiquitously expressed guanine nucleotide exchange factor of 200 kDa that activates Rap1 both in vivo and in vitro. This exchange factor has two putative regulatory domains: a domain with an amino acid sequence related to cAMP-binding 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 cAMP 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 negative regulatory domain. However, PDZ-GEF1 does not interact with cAMP or cGMP. Interestingly, PDZ-GEF1 also activates Rap2, a close relative of Rap1. This 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 and Rap2, that is controlled by a negative regulatory domain.
authors.affiliation: Laboratory for Physiological Chemistry, Center for Biomedical Genetics, Utrecht University, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: de Rooij
authors.forename: N M
authors.initials: NM
authors.lastname: Boenink
authors.forename: M
authors.initials: M
authors.lastname: van Triest
authors.forename: R H
authors.initials: RH
authors.lastname: Cool
authors.forename: A
authors.initials: A
authors.lastname: Wittinghofer
authors.forename: J L
authors.initials: JL
authors.lastname: Bos
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins; D010802:Phylogeny; D017386:Sequence Homology, Amino Acid; D020668:rap GTP-Binding Proteins / Q000378:metabolism*; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D009419:Nerve Tissue Proteins; C403525:RAPGEF2 protein, human; C116756:RAP2A protein, human; D020668:rap GTP-Binding Proteins; D020827:rap1 GTP-Binding Proteins