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Cloning and characterization of GEF-H1, a microtubule-associated guanine nucleotide exchange factor for Rac and Rho GTPases.

The Rho-related small GTPases are critical elements involved in regulation of signal transduction cascades from extracellular stimuli to cell nucleus and cytoskeleton. The Dbl-like guanine nucleotide exchange factors (GEF) have been implicated in direct activation of these GTPases. Here we have identified a new member of the Dbl family, GEF-H1, by screening a human HeLa cell cDNA library. GEF-H1 encodes a 100-kDa protein containing the conserved structural array of a Dbl homology domain in tandem with a pleckstrin homology domain and is most closely related to the lfc oncogene, but additionally it contains a unique coiled-coil domain at the carboxyl terminus. Biochemical analysis reveals that GEF-H1 is capable of stimulating guanine nucleotide exchange of Rac and Rho but is inactive toward Cdc42, TC10, or Ras. Moreover, GEF-H1 binds to Rac and Rho proteins in both the GDP- and guanosine 5'-3-O-(thio)triphosphate-bound states without detectable affinity for Cdc42 or Ras. Immunofluorescence reveals that GEF-H1 colocalizes with microtubules through the carboxyl-terminal coiled-coil domain. Overexpression of GEF-H1 in COS-7 cells results in induction of membrane ruffles. These results suggest that GEF-H1 may have a direct role in activation of Rac and/or Rho and in bringing the activated GTPase to specific target sites such as microtubules.

Pubmed ID: 9857026

Authors

  • Ren Y
  • Li R
  • Zheng Y
  • Busch H

Journal

The Journal of biological chemistry

Publication Data

December 25, 1998

Associated Grants

  • Agency: NIGMS NIH HHS, Id: GM53943

Mesh Terms

  • 3T3 Cells
  • Amino Acid Sequence
  • Animals
  • COS Cells
  • Enzyme Activation
  • Fluorescent Antibody Technique
  • GTP Phosphohydrolases
  • GTP-Binding Proteins
  • GTPase-Activating Proteins
  • Gene Library
  • Guanine Nucleotide Exchange Factors
  • Guanine Nucleotides
  • Humans
  • Mice
  • Microtubule-Associated Proteins
  • Molecular Sequence Data
  • Open Reading Frames
  • Proteins
  • Proto-Oncogene Proteins
  • Recombinant Proteins
  • Rho Guanine Nucleotide Exchange Factors
  • Sequence Homology, Amino Acid
  • rac GTP-Binding Proteins
  • ras GTPase-Activating Proteins
  • ras Guanine Nucleotide Exchange Factors
  • rho GTP-Binding Proteins