Regulation of the Cool/Pix proteins. Key binding partners of the Cdc42/Rac targets, the p21-activated kinases

Qiyu Feng, John Albeck, Richard A. Cerione, Wannian Yang

Research output: Contribution to journalArticlepeer-review

89 Scopus citations


The Cool (cloned-out of library)/Pix (for PAK-interactive exchange factor) proteins directly bind to members of the PAK family of serine/threonine kinases and regulate their activity. Three members of the Cool/Pix family have shown distinct regulatory activities: (i) p50 Cool-1 inhibits Cdc42/Rac-stimulated PAK activity, (ii) p85 Cool-1/β-Pix has a permissive effect on Cdc42/Rac-stimulated activity, and (iii) p90 Cool-2/α-Pix strongly activates PAK. We initially suspected that these different functional effects were due to a binding interaction that occurs at the carboxyl-terminal ends of the larger Cool/ Pix proteins, thus enabling them to stimulate (or at least permit) rather than inhibit PAK activity. This led to the identification of the Cat proteins (for Cool-associated tyrosine phosphosubstrates). However, here we show that the Cat proteins bind to the carboxyl-terminal ends of p85 Cool-1 (residues 523-546) and Cool-2 (residues 647-670), and that the binding of Cat to Cool-2 in fact is not necessary for the Cool-2-mediated activation of PAK. Rather, an 18-amino acid region, designated T1, that is present in the Cool-1 proteins, but missing in Cool-2, is essential for controlling the regulation of PAK activity by Cool-1/β-Pix in vivo. Deletion of T1 yielded a p85 Cool-1 molecule that mimicked the Cool-2 protein and was capable of strongly stimulating PAK activity. However, when T1 was added to Cool-2, the ability of Cool-2 to directly activate PAK was lost. We conclude that T1 represents a novel regulatory domain that accounts for the specific functional effects on PAK activity exhibited by the different members of the Cool/Pix family.

Original languageEnglish (US)
Pages (from-to)5644-5650
Number of pages7
JournalJournal of Biological Chemistry
Issue number7
StatePublished - Feb 15 2002
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry


Dive into the research topics of 'Regulation of the Cool/Pix proteins. Key binding partners of the Cdc42/Rac targets, the p21-activated kinases'. Together they form a unique fingerprint.

Cite this