A growing family of guanine nucleotide exchange factors is responsible for activation of Ras-family GTPases.
GTPases of the Ras subfamily regulate a diverse array of cellular-signaling pathways, coupling extracellular signals to the intracellular response machinery. Guanine nucleotide exchange factors (GEFs) are primarily responsible for linking cell-surface receptors to Ras protein activation. They do this by catalyzing the dissociation of GDP from the inactive Ras proteins. GTP can then bind and induce a conformational change that permits interaction with downstream effectors. Over the past 5 years, approximately 20 novel Ras-family GEFs have been identified and characterized. These data indicate that a variety of different signaling mechanisms can be induced to activate Ras, enabling tyrosine kinases, G-protein-coupled receptors, adhesion molecules, second messengers, and various protein-interaction modules to relocate and/or activate GEFs and elevate intracellular Ras-GTP levels. This review discusses the structure and function of the catalytic or CDC25 homology domain common to almost all Ras-family GEFs. It also details our current knowledge about the regulation and function of this rapidly growing family of enzymes that include Sos1 and 2, GRF1 and 2, CalDAG-GEF/GRP1-4, C3G, cAMP-GEF/Epac 1 and 2, PDZ-GEFs, MR-GEF, RalGDS family members, RalGPS, BCAR3, Smg GDS, and phospholipase C(epsilon).
Quilliam
Lawrence A
LA
Department of Biochemistry and Molecular, Biology and Walther Oncology Center, Indiana University School of Medicine, Indianapolis 46202, USA.
Rebhun
John F
JF
Castro
Ariel F
AF
D000595:Amino Acid Sequence; D000818:Animals; D004789:Enzyme Activation; D006801:Humans; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000209:etiology; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D020703:ras GTPase-Activating Proteins / Q000378:metabolism; D020663:ras Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*; D020666:ras-GRF1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D020703:ras GTPase-Activating Proteins; D020663:ras Guanine Nucleotide Exchange Factors; D020666:ras-GRF1; D018631:ras Proteins