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First published online 6 February 2007
doi: 10.1242/jcs.03373

Journal of Cell Science 120, 792-801 (2007)
Published by The Company of Biologists 2007
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Research Article

PI-3-kinase-dependent membrane recruitment of centaurin-{alpha}2 is essential for its effect on ARF6-mediated actin cytoskeleton reorganisation

Kanamarlapudi Venkateswarlu*, Kevin G. Brandom and Hongruo Yun

Department of Pharmacology, The University of Bristol, Bristol, BS8 1TD, UK

* Author for correspondence (e-mail: k.venkateswalru{at}bristol.ac.uk)

Accepted 8 December 2006

GTPase activating proteins (GAPs) of the centaurin family regulate the actin cytoskeleton and vesicle trafficking through inactivation of the ADP-ribosylation factor (ARF) family of small GTP-binding proteins. We report the functional characterisation of centaurin-{alpha}2, which is structurally related to the centaurin-{alpha}1 ARF6 GAP. centaurin-{alpha}2 contains an N-terminal GAP domain followed by two pleckstrin homology (PH) domains (N-PH and C-PH). In vitro, GFP-centaurin-{alpha}2 specifically binds the phosphatidylinositol (PI) 3-kinase lipid products, PI 3,4-P2 and PI 3,4,5-P3 (PIP3), through its C-terminal PH domain. In agreement with this observation, GFP-centaurin-{alpha}2 was recruited to the plasma membrane from the cytosol in EGF-stimulated cells in a PI-3-kinase-dependent manner. Moreover, the C-PH domain is sufficient and necessary for membrane recruitment of centaurin-{alpha}2. centaurin-{alpha}2 shows sustained kinetics of PI-3-kinase-mediated membrane recruitment in EGF-stimulated cells, owing to its binding to PI 3,4-P2. centaurin-{alpha}2 prevents ARF6 translocation to, and cortical actin formation at, the plasma membrane, which are phenotypic indications for ARF6 activation in EGF-stimulated cells. Moreover, the constitutively active mutant of ARF6 reverses the effect of centaurin-{alpha}2 on cortical actin formation. The membrane targeted centaurin-{alpha}2 is constitutively active. Together, these studies indicate that centaurin-{alpha}2 is recruited in a sustained manner to the plasma membrane through binding to PI 3,4-P2 and thereby regulates actin reorganisation via ARF6.

Key words: centaurin-{alpha}2, PI 3-kinase, PIP3, PI 3, 4-P2, ARF6, Actin, GAP


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