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GIT1 Activates p21-Activated Kinase through a Mechanism Independent of p21 Binding

GSK-IMCB Group, Institute of Molecular and Cell Biology, Singapore 117609, Singapore,¹ Institute of Neurology, University College London, London WC1N 1PJ, United Kingdom²

Received 5 August 2003/ Returned for modification 23 September 2003/ Accepted 30 January 2004

p21-activated kinases (PAKs) associate with a guanine nucleotide exchange factor, Pak-interacting exchange factor (PIX), which in turn binds the paxillin-associated adaptor GIT1 that targets the complex to focal adhesions. Here, a detailed structure-function analysis of GIT1 reveals how this multidomain adaptor also participates in activation of PAK. Kinase activation does not occur via Cdc42 or Rac1 GTPase binding to PAK. The ability of GIT1 to stimulate PAK autophosphorylation requires the participation of the GIT N-terminal Arf-GAP domain but not Arf-GAP activity and involves phosphorylation of PAK at residues common to Cdc42-mediated activation. Thus, the activation of PAK at adhesion complexes involves a complex interplay between the kinase, Rho GTPases and protein partners that provide localization cues.

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