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, Christina Bark

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62 Scopus citations


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 β-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 β-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 β-cells by phosphorylating Munc18-1 at a biochemical step immediately prior to vesicle fusion.

Original languageEnglish (US)
Pages (from-to)29534-29541
Number of pages8
JournalJournal of Biological Chemistry
Issue number28
StatePublished - Jul 9 2004
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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