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A conserved C-terminal domain of EFA6-family ARF6-guanine nucleotide exchange factors induces lengthening of microvilli-like membrane protrusions

Valérie Derrien^1,*, Carole Couillault^2,*, Michel Franco³, Stéphanie Martineau², Philippe Montcourrier⁴, Rémi Houlgatte² and Philippe Chavrier^1,

¹ Laboratoire de la Dynamique de la Membrane et du Cytosquelette, UMR 144, Centre National de la Recherche Scientifique, Institut Curie, Section Recherche. 26 rue d'Ulm, 75241 Paris Cedex 5, France
² Centre d'Immunologie INSERM/CNRS de Marseille-Luminy, Case 906, 13288 Marseille Cedex 9, France
³ Institut de Pharmacologie Moléculaire et Cellulaire, UPR411, CNRS, 660 route des Lucioles, Sophia-Antipolis, 06650 Valbonne, France
⁴ CNRS UMR 5539, Université Montpellier II, 34095 Montpellier Cedex 5, France
^* These authors contributed equally

Author for correspondence (e-mail: philippe.chavrier{at}curie.fr )

Accepted 1 May 2002

We recently reported the identification of EFA6 (exchange factor for ARF6), a brain-specific Sec7-domain-containing guanine nucleotide exchange factor that works specifically on ARF6. Here, we have characterized the product of a broadly expressed gene encoding a novel 1056 amino-acid protein that we have named EFA6B. We show that EFA6B, which contains a Sec7 domain that is highly homologous to EFA6, works as an ARF6-specific guanine exchange factor in vitro. Like EFA6, which will be referred to as EFA6A from now on, EFA6B is involved in membrane recycling and colocalizes with ARF6 in actin-rich membrane ruffles and microvilli-like protrusions on the dorsal cell surface in transfected baby hamster kidney cells. Strikingly, homology between EFA6A and EFA6B is not limited to the Sec7 domain but extends to an adjacent pleckstrin homology (PH) domain and a 150 amino-acid C-terminal region containing a predicted coiled coil motif. Association of EFA6A with membrane ruffles and microvilli-like structures depends on the PH domain, which probably interacts with phosphatidylinositol 4,5-biphosphate. Moreover, we show that overexpression of the PH domain/C-terminal region of EFA6A or EFA6B in the absence of the Sec7 domain promotes lengthening of dorsal microvillar protrusions. This morphological change requires the integrity of the coiled-coil motif. Lastly, database analysis reveals that the EFA6-family comprises at least four members in humans and is conserved in multicellular organisms throughout evolution. Our results suggest that EFA6 family guanine exchange factors are modular proteins that work through the coordinated action of the catalytic Sec7 domain to promote ARF6 activation, through the PH domain to regulate association with specific subdomains of the plasma membrane and through the C-terminal region to control actin cytoskeletal reorganization.

Key words: ADP-ribosylation factor 6, Sec7 domain, Actin cytoskeleton, Endocytosis, Guanine nucleotide exchange factor

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