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J. Biol. Chem., Vol. 282, Issue 27, 19565-19574, July 6, 2007

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Activation of p61Hck Triggers WASp- and Arp2/3-dependent Actin-comet Tail Biogenesis and Accelerates Lysosomes^*

Claire Vincent, Isabelle Maridonneau-Parini¹, Christophe Le Clainche, Pierre Gounon^¶, and Arnaud Labrousse

From the Institut de Pharmacologie et de Biologie Structurale, CNRS UMR5089, 31077 Toulouse Cedex 04, France, Dynamique du Cytosquelette et Motilité, Laboratoire d'Enzymologie et de Biochimie Structurales, CNRS, 91198 Gif-sur-Yvette, France, and ^¶Centre Commun de Microscopie, Faculté des Sciences, 06108 Nice Cedex 2, France

Secretory lysosomes exist in few cell types, but various mechanisms are involved to ensure their mobilization within the cytoplasm. In phagocytes, lysosome exocytosis is a regulated phenomenon at least in part under the control of the phagocyte-specific and lysosome-associated Src-kinase p61Hck (hematopoietic cell kinase). We show here that p61Hck activation triggered polymerization of actin at the membrane of lysosomes, which resulted in F-actin structures similar to comet tails observed on endocytic vesicles. We correlated this actin-comet biogenesis to a 35% acceleration of p61Hck-lysosomes in cells, which was dependent on actin polymerization and required an intact microtubular network. It was possible to initiate the formation of actin tails on p61Hck-positive lysosomes and on p61Hck-associated latex beads incubated in human phagocyte cytosolic extracts. The in vitro reconstitution on beads indicated that other lysosomal proteins were dispensable in this mechanism. The de novo actin polymerization process was functionally dependent on the kinase activity of Hck, WASp, the Arp2/3 complex, and Cdc42 but not Rac or Rho. Thus, we identified p61Hck as the first lysosomal protein able to recruit the molecular machinery responsible for actin tail formation. Altogether, our results suggest a new mechanism for lysosome motility involving p61Hck, actin-comet tail biogenesis, and the microtubule network.

Received for publication, February 20, 2007 , and in revised form, May 4, 2007.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Institut de Pharmacologie et de Biologie Structurale, CNRS-UMR5089, 205 route de Narbonne, 31077 Toulouse Cedex 04, France. Tel.: 33-5-61175458; Fax: 33-5-61175994; E-mail: Isabelle.Maridonneau-Parini{at}ipbs.fr.

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