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Novel regulatory mechanisms for the Dbl family guanine nucleotide exchange factor Cool-2/alpha-Pix.

The Cool-2 (cloned-out of library-2) protein (identical to alpha-Pix for Pak-interactive exchange factor) has been implicated in various biological responses including chemoattractant signaling and in certain forms of mental retardation. We show that when Cool-2 exists as a dimer, it functions as a Rac-specific guanine nucleotide exchange factor (GEF). Dimerization of Cool-2 enables its Dbl (diffuse B-cell lymphoma) and pleckstrin homology domains to work together (in trans) to bind specifically to Rac-GDP. Dissociation of dimeric Cool-2 into its monomeric form allows it to act as a GEF for Cdc42 as well as for Rac. The binding of either PAK (p21-activated kinase) or Cbl (Casitas B-lymphoma) to the SH3 domain of monomeric Cool-2 is necessary for the functional interactions between GDP-bound Cdc42 or Rac and the Cool-2 monomer. The betagamma subunit complex of large GTP-binding proteins, by interacting with PAK, stimulates the dissociation of the Cool-2 dimer and activates its GEF activity for Cdc42. Overall, these findings highlight novel mechanisms by which extracellular signals can direct the specific activation of Rac versus Cdc42 by Cool-2/alpha-Pix.

Pubmed ID: 15306850

Authors

  • Feng Q
  • Baird D
  • Cerione RA

Journal

The EMBO journal

Publication Data

September 1, 2004

Associated Grants

None

Mesh Terms

  • Animals
  • COS Cells
  • Cell Cycle Proteins
  • Dimerization
  • Guanine Nucleotide Exchange Factors
  • In Vitro Techniques
  • Kinetics
  • Models, Biological
  • Protein Binding
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases
  • Recombinant Proteins
  • Rho Guanine Nucleotide Exchange Factors
  • cdc42 GTP-Binding Protein
  • p21-Activated Kinases
  • rac GTP-Binding Proteins
  • src Homology Domains