QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

doi: 10.1242/10.1242/jcs.00080

This Article Figures Only Full Text Full Text (PDF) Movie Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wells, C. M. Articles by Ridley, A. J. Search for Related Content PubMed PubMed Citation Articles by Wells, C. M. Articles by Ridley, A. J.

PAK4 is activated via PI3K in HGF-stimulated epithelial cells

Claire M. Wells¹, Arie Abo^2,* and Anne J. Ridley^1,3,

¹ Ludwig Institute for Cancer Research, Royal Free and University College Medical School Branch, 91 Riding House Street, London WIW 7BS, UK
² Onyx Pharmaceuticals, 3031 Research Drive, Richmond, CA 94806, USA
³ Department of Biochemistry and Molecular Biology, University College London, Gower Street, London, UK
^* Present address: PPD Discovery, 1505 O'Brien Dr Menlo Park, CA 94025, USA

Address for correspondence (e-mail: anne{at}ludwig.ucl.ac.uk)

Accepted 1 August 2002

The p21-activated kinases (PAKs) are divided into two subgroups based on sequence homology. Group 1 PAKs (PAK1-3) are involved in cell migration, and are activated by pro-migratory stimuli and by Cdc42/Rac GTPases. In contrast, little is known about the regulation of the recently identified group II PAKs (PAK4-6). Here we report that PAK4 is activated by HGF, a migratory stimulus for epithelial cells. In unstimulated MDCK cells, activated PAK4 induces a decrease in stress fibres, and when cells are stimulated with HGF, it induces a loss of focal complexes and cell rounding. This response is dependent on PAK4 kinase activity but does not require Cdc42 interaction. Activated PAK4 localises to the cell periphery but not specifically in lamellipodia, and HGF induces localisation of wild-type PAK4 to the cell periphery. LY294002, a phosphoinositide 3-kinase (PI3K) inhibitor, inhibits HGF-induced PAK4 kinase activation, relocalisation, and cell rounding. However, the isolated C-terminal kinase domain of PAK4 can induce cell rounding in the presence of LY294002, suggesting that the N-terminal region acts as a negative regulator of PAK4 activity. These results indicate that HGF stimulates PAK4 through PI3K, and that PAK4 could contribute to HGF-induced changes in actin organisation and cell-substratum adhesion.

Key words: p21-activated kinase, Phosphoinositide 3-kinase, PAK4, HGF, Actin, Cytoskeleton, Focal complexes

This article has been cited by other articles:

				C. Gamell, N. Osses, R. Bartrons, T. Ruckle, M. Camps, J. L. Rosa, and F. Ventura BMP2 induction of actin cytoskeleton reorganization and cell migration requires PI3-kinase and Cdc42 activity J. Cell Sci., December 1, 2008; 121(23): 3960 - 3970. [Abstract] [Full Text] [PDF]

				M. G. Callow, S. Zozulya, M. L. Gishizky, B. Jallal, and T. Smeal PAK4 mediates morphological changes through the regulation of GEF-H1 J. Cell Sci., May 1, 2005; 118(9): 1861 - 1872. [Abstract] [Full Text] [PDF]

				M. C. Wilkes, S. J. Murphy, N. Garamszegi, and E. B. Leof Cell-Type-Specific Activation of PAK2 by Transforming Growth Factor {beta} Independent of Smad2 and Smad3 Mol. Cell. Biol., December 1, 2003; 23(23): 8878 - 8889. [Abstract] [Full Text] [PDF]

				J. Qu, X. Li, B. G. Novitch, Y. Zheng, M. Kohn, J.-M. Xie, S. Kozinn, R. Bronson, A. A. Beg, and A. Minden PAK4 Kinase Is Essential for Embryonic Viability and for Proper Neuronal Development Mol. Cell. Biol., October 15, 2003; 23(20): 7122 - 7133. [Abstract] [Full Text] [PDF]