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Vol. 13, Issue 8, 2946-2962, August 2002
Department of Biochemistry, School of Medicine, University of
Crete, GR-71110 Heraklion, Greece
The family of p21-activated kinases (PAKs) have been implicated in
the rearrangement of actin cytoskeleton by acting downstream of the
small GTPases Rac and Cdc42. Here we report that even though Cdc42/Rac1
or Akt are not activated, phosphatidylinositol-3 (PI-3) kinase
activation induces PAK1 kinase activity. Indeed, we demonstrate that
PI-3 kinase associates with the N-terminal regulatory domain of PAK1
(amino acids 67-150) leading to PAK1 activation. The association of
the PI-3 kinase with the Cdc42/Rac1 binding-deficient PAK1(H83,86L) confirms that the small GTPases are not involved in the PI-3
kinase-PAK1 interaction. Furthermore, PAK1 was activated in cells
expressing the dominant-negative forms of Cdc42 or Rac1.
Additionally, we show that PAK1 phosphorylates actin, resulting in the
dissolution of stress fibers and redistribution of microfilaments. The
phosphorylation of actin was inhibited by the kinase-dead PAK1(K299R)
or the PAK1 autoinhibitory domain (PAK1(83-149)), indicating that PAK1
was responsible for actin phosphorylation. We conclude that the
association of PI-3 kinase with PAK1 regulates PAK1 kinase activity
through a Cdc42/Rac1-independent mechanism leading to actin
phosphorylation and cytoskeletal reorganization.
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