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J. Biol. Chem., Vol. 276, Issue 20, 17347-17353, May 18, 2001

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The Mechanism of PAK Activation
AUTOPHOSPHORYLATION EVENTS IN BOTH REGULATORY AND KINASE DOMAINS CONTROL ACTIVITY^*

Claire Chong, Lydia Tan, Louis Lim^§, and Edward Manser^¶

From the  Glaxo-IMCB Group, Institute of Molecular and Cell Biology, 30 Medical Dr., Singapore 117609 and the ^§ Miriam Marks Department of Neurochemistry, Institute of Neurology, 1 Wakefield St., University College, London WC1N 1PJ, United Kingdom

The p21-activated kinases (PAKs), in common with many kinases, undergo multiple autophosphorylation events upon interaction with appropriate activators. The Cdc42-induced phosphorylation of PAK serves in part to dissociate the kinase from its partners PIX and Nck. Here we investigate in detail how autophosphorylation events affect the catalytic activity of PAK by altering the autophosphorylation sites in both - and PAK. Both in vivo and in vitro analyses demonstrate that, although most phosphorylation events in the PAK N-terminal regulatory domain play no direct role in activation, a phosphorylation of PAK serine 144 or PAK serine 139, which lie in the kinase inhibitory domain, significantly contribute to activation. By contrast, sphingosine-mediated activation is independent of this residue, indicating a different mode of activation. Thus two autophosphorylation sites direct activation while three others control association with focal complexes via PIX and Nck.

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