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J. Biol. Chem., Vol. 279, Issue 28, 29534-29541, July 9, 2004

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Cyclin-dependent Kinase 5 Associated with p39 Promotes Munc18-1 Phosphorylation and Ca²⁺-dependent Exocytosis^*

Lena Lilja, Jenny Ulrika Johansson, Jesper Gromada, Slavena Andrea Mandic, Gabriel Fried¶, Per-Olof Berggren||, and Christina Bark

From the The Rolf Luft Center for Diabetes Research, Department of Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, SE-171 76 Stockholm, Sweden, Lilly Research Laboratories, Essener Strasse 93, D-22419 Hamburg, Germany, and the ^¶Department of Woman and Child Health, Karolinska Institutet, Karolinska University Hospital, SE-171 76 Stockholm, Sweden

Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine protein kinase that requires association with a regulatory protein, p35 or p39, to form an active enzyme. Munc18-1 plays an essential role in membrane fusion, and its function is regulated by phosphorylation. We report here that both p35 and p39 were expressed in insulin-secreting -cells, where they exhibited individual subcellular distributions and associated with membranous organelles of different densities. Overexpression of Cdk5, p35, or p39 showed that Cdk5 and p39 augmented Ca²⁺-induced insulin exocytosis. Suppression of p39 and Cdk5, but not of p35, by antisense oligonucleotides selectively inhibited insulin exocytosis. Transient transfection of primary -cells with Munc18-1 templates mutated in potential Cdk5 or PKC phosphorylation sites, in combination with Cdk5 and the different Cdk5 activators, suggested that Cdk5/p39-promoted Ca²⁺-dependent insulin secretion from primary -cells by phosphorylating Munc18-1 at a biochemical step immediately prior to vesicle fusion.

Received for publication, November 20, 2003 , and in revised form, April 22, 2004.

^* This work was supported by Funds from Karolinska Institutet, Edla and Erik Smedbergs Foundation, Swedish Society for Medical Research, Berth von Kantzow's Foundation, The Family Persson Foundation, Swedish Research Council, The Swedish Diabetes Association, The Novo Nordisk Foundation, National Institutes of Health Grant DK-58508, Clas Groshinskys Foundation, Sigurd and Elsa Goljes Foundation, Ragnhild and Einar Lundströms Foundation, Loo and Hans Ostermans Foundation, and the Juvenile Diabetes Research Foundation. 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.

^|| To whom correspondence should be addressed: The Rolf Luft Center for Diabetes Research L3, Dept. of Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, SE-171 76 Stockholm, Sweden. Tel.: 46-8-517-757-31; Fax: 46-8-517-794-50; E-mail: per-olof.berggren{at}molmed.ki.se.

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