Molecular Cell
Volume 40, Issue 3, 12 November 2010, Pages 493-500
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Short Article
Phosphoinositides Are Essential Coactivators for p21-Activated Kinase 1

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Summary

Phospholipid-enriched membranes such as the plasma membrane can serve as direct regulators of kinase signaling. Pak1 is involved in growth factor signaling at the plasma membrane, and its dysregulation is implicated in cancer. Pak1 adopts an autoinhibited conformation that is relieved upon binding to membrane-bound Rho GTPases Rac1 or Cdc42, but whether lipids also regulate Pak1 in vivo is unknown. We show here that phosphoinositides, particularly PIP2, potentiate Rho-GTPase-mediated Pak1 activity. A positively charged region of Pak1 binds to phosphoinositide-containing membranes, and this interaction is essential for membrane recruitment and activation of Pak1 in response to extracellular signals. Our results highlight an active role for lipids as allosteric regulators of Pak1 and suggest that Pak1 is a “coincidence detector” whose activation depends on GTPases present in phosphoinositide-rich membranes. These findings expand the role of phosphoinositides in kinase signaling and suggest how altered phosphoinositide metabolism may upregulate Pak1 activity in cancer cells.

Highlights

► PIP2 potentiates Rac1-induced Pak1 activation ► A basic region in the N-terminal domain of Pak1 mediates PIP2 binding ► PIP2 binding is necessary for recruitment of Pak1 to the plasma membrane ► PIP2 binding is essential for Pak1 activation by growth factor stimulation

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2

These authors contributed equally to this work

3

Present address: Metanomics GmbH, Tegeler Weg 33, 10589 Berlin, Germany