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J Biol Chem, Vol. 274, Issue 46, 32565-32573, November 12, 1999
From the Departments of Immunology and Cell Biology, The Scripps
Research Institute, La Jolla, California 92037
p21-activated kinases (Pak)/Ste20 kinases are
regulated in vitro and in vivo by the small
GTP-binding proteins Rac and Cdc42 and lipids, such as sphingosine,
which stimulate autophosphorylation and phosphorylation of exogenous
substrates. The mechanism of Pak activation by these agents remains
unclear. We investigated Pak kinase activation in more detail to gain
insight into the interplay between the GTPase/sphingosine binding, an
intramolecular inhibitory interaction, and autophosphorylation. We
present biochemical evidence that an autoinhibitory domain (ID)
contained within amino acid residues 67-150 of Pak1 interacts with the
carboxyl-terminal kinase domain and that this interaction is regulated
in a GTPase-dependent fashion. Cdc42- and
sphingosine-stimulated Pak1 activity can be inhibited in
trans by recombinant ID peptide, indicating similarities in
their mode of activation. However, Pak1, which was autophosphorylated in response to either GTPase or sphingosine, is highly active and is
insensitive to inhibition by the ID peptide. We identified phospho-acceptor site threonine 423 in the kinase activation loop as a
critical determinant for the sensitivity to autoinhibition and
enzymatic activity. Phosphorylation studies suggested that the
stimulatory effect of both GTPase and sphingosine results in exposure
of the activation loop, making it accessible for intermolecular phosphorylation.
Identification of a Central Phosphorylation Site in p21-activated
Kinase Regulating Autoinhibition and Kinase Activity
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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