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First published online 12 April 2005
doi: 10.1242/jcs.02313

Journal of Cell Science 118, 1861-1872 (2005)
Published by The Company of Biologists 2005
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Research Article

PAK4 mediates morphological changes through the regulation of GEF-H1

Marinella G. Callow1,*, Sergey Zozulya1,{ddagger}, Mikhail L. Gishizky1,§, Bahija Jallal1,¶ and Tod Smeal1,**,{ddagger}{ddagger}

1 SUGEN Incorporated, 230 East Grand Avenue, South San Francisco, CA 94080, USA

{ddagger}{ddagger} Author for correspondence (e-mail: tod.smeal{at}pfizer.com)

Accepted 7 February 2005

Precise spatial and temporal regulation of Rho GTPases is required in controlling F-actin-based changes in cell morphology. The molecular mechanisms through which microtubules (MTs) modulate the activity of RhoGTPases and regulate the actin cytoskeleton are unclear. Here we show that p21-activated-kinase 4 (PAK4) mediates morphological changes through its association with the Rho-family guanine nucleotide exchange factor (GEF), GEF-H1. We show that this association is dependent upon a novel GEF-H1 interaction domain (GID) within PAK4. Further, we show that PAK4-mediated phosphorylation of Ser810 acts as a switch to block GEF-H1-dependent stress fiber formation while promoting the formation of lamellipodia in NIH-3T3 cells. We found that the endogenous PAK4-GEF-H1 complex associates with MTs and that PAK4 phosphorylation of MT-bound GEF-H1 releases it into the cytoplasm of NIH-3T3 cells, which coincides with the dissolution of stress fibers. Our observations propose a novel role for PAK4 in GEF-H1-dependent crosstalk between MTs and the actin cytoskeleton.

Key words: p21-activated kinase, PAK4, GEF-H1, Cdc42, Rac, Rho, Cytoskeleton, F-actin, Phosphorylation


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