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J. Biol. Chem., Vol. 278, Issue 48, 47434-47440, November 28, 2003

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PIAS1-mediated Sumoylation of Focal Adhesion Kinase Activates Its Autophosphorylationn^*

Gress Kadaré, Madeleine Toutant, Etienne Formstecher, Jean-Christophe Corvol, Michèle Carnaud, Marie-Claude Boutterin, and Jean-Antoine Girault

From the INSERM/UPMC U536, Institut National de la Santé et de la Recherche Médicale et Université Pierre et Marie Curie, Institut du Fer à Moulin, 17 rue du Fer à Moulin, 75005 Paris, France

Focal adhesion kinase (FAK) is a protein tyrosine kinase enriched in focal adhesions, which plays a critical role in integrin-dependent cell motility and survival. The crucial step in its activation is autophosphorylation on Tyr-397, which promotes the recruitment of several enzymes including Src family kinases and the activation of multiple signaling pathways. We found in a yeast two-hybrid screen that the N-terminal domain of FAK interacted with protein inhibitor of activated STAT1 (PIAS1). This interaction was confirmed and shown to be direct using in vitro assays. PIAS1 was co-immunoprecipitated with FAK from transfected cells and brain extracts. PIAS1 has recently been recognized as a small ubiquitin-like modifier (SUMO) ligase. In the presence of PIAS1 and SUMO-1, FAK was sumoylated in intact cells, whereas PYK2, a closely related enzyme, was not. Sumoylation occurred on Lys-152, a residue conserved in FAK during evolution. Sumoylated FAK, like PIAS1, was recovered predominantly from the nuclear fraction. Sumoylation did not require the catalytic activity or autophosphorylation of FAK. In contrast, sumoylation increased dramatically the ability of FAK to autophosphorylate in intact cells and in immune precipitate kinase assays. Endogenous FAK was sumoylated in the presence of PIAS1 and SUMO-1 independently of cell adhesion, and autophosphorylation of sumoylated FAK was persistently increased in suspended cells. These observations show that sumoylation controls the activity of a protein kinase and suggest that FAK may play a novel role in signaling between the plasma membrane and the nucleus.

Received for publication, August 4, 2003 , and in revised form, September 11, 2003.

^* This work was supported by grants from INSERM, Human Frontiers Science Program, Fondation Schlumberger pour l'Enseignement et la Recherche (Dotation Gruener-Schlumberger), Fondation Liliane Bettencourt-Schueller, Fondation pour la Recherche Médicale, and Association pour la Recherche contre le Cancer. 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.

Present address: Hybrigenics SA, 3–5 impasse Reille, 75014 Paris, France.

To whom correspondence should be addressed. E-mail: girault{at}ifm.inserm.fr.

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