A growing family of guanine nucleotide exchange factors is responsible for activation of Ras-family GTPases

Prog Nucleic Acid Res Mol Biol. 2002;71:391-444. doi: 10.1016/s0079-6603(02)71047-7.


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).

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Enzyme Activation
  • Humans
  • Molecular Sequence Data
  • Neoplasms / etiology
  • Protein Structure, Tertiary
  • Sequence Homology, Amino Acid
  • ras GTPase-Activating Proteins / metabolism
  • ras Guanine Nucleotide Exchange Factors / chemistry
  • ras Guanine Nucleotide Exchange Factors / genetics
  • ras Guanine Nucleotide Exchange Factors / metabolism*
  • ras Proteins / metabolism*
  • ras-GRF1 / chemistry
  • ras-GRF1 / genetics
  • ras-GRF1 / metabolism


  • ras GTPase-Activating Proteins
  • ras Guanine Nucleotide Exchange Factors
  • ras-GRF1
  • ras Proteins