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Published 1 March 2004. doi:10.1083/jcb.200307032
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 164, Number 5, 653-659
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Phosphoinositide binding and phosphorylation act sequentially in the activation mechanism of ezrin



Bruno T. Fievet1, Alexis Gautreau1, Christian Roy2, Laurence Del Maestro1, Paul Mangeat2, Daniel Louvard1, and Monique Arpin1

1 Laboratoire de Morphogenèse et Signalisation Cellulaires, UMR144 Centre National de la Recherche Scientifique (CNRS), Institut Curie, 75248 Paris, Cedex 05, France
2 Université Montpellier, UMR 5539 CNRS, 34095 Montpellier, Cedex 05, France

Address correspondence to Monique Arpin, Laboratoire de Morphogenèse et Signalisation Cellulaires, UMR144 CNRS, 26 Rue d'Ulm, Institut Curie, Paris, Cedex 05, 75248 France. Tel.: 33-1-4234-6372. Fax: 33-1-4234-6377. email: marpin{at}curie.fr

Ezrin, a membrane–actin cytoskeleton linker, which participates in epithelial cell morphogenesis, is held inactive in the cytoplasm through an intramolecular interaction. Phosphatidylinositol 4,5-bisphosphate (PIP2) binding and the phosphorylation of threonine 567 (T567) are involved in the activation process that unmasks both membrane and actin binding sites. Here, we demonstrate that ezrin binding to PIP2, through its NH2-terminal domain, is required for T567 phosphorylation and thus for the conformational activation of ezrin in vivo. Furthermore, we found that the T567D mutation mimicking T567 phosphorylation bypasses the need for PIP2 binding for unmasking both membrane and actin binding sites. However, PIP2 binding and T567 phosphorylation are both necessary for the correct apical localization of ezrin and for its role in epithelial cell morphogenesis. These results establish that PIP2 binding and T567 phosphorylation act sequentially to allow ezrin to exert its cellular functions.

Key Words: ERM proteins; PIP2; actin cytoskeleton; epithelial cell morphogenesis

Abbreviations used in this paper: C-ERMAD, COOH-terminal ERM association domain; ERM, ezrin/radixin/moesin; N-ERMAD, NH2-terminal ERMAD; PH, pleckstrin homology; PIP2, phosphatidylinositol 4,5-bisphosphate; VSV G, vesicular stomatitis virus glycoprotein; wt, wild-type.


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