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Novel regulatory mechanisms for the Dbl family guanine nucleotide exchange factor Cool‐2/α‐Pix
Author(s) -
Feng Qiyu,
Baird Daniel,
Cerione Richard A
Publication year - 2004
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600331
Subject(s) - biology , guanine nucleotide exchange factor , guanine , nucleotide , genetics , gene , signal transduction
The Cool‐2 ( c loned‐ o ut o f l ibrary‐2) protein (identical to α‐Pix for P ak‐ i nteractive e x change 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 ( d iffuse B ‐cell l ymphoma) 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 ( p 21‐ a ctivated k inase) or Cbl ( C asitas B ‐ l ymphoma) 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 βγ 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/α‐Pix.