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First published online 16 November 2004
doi: 10.1242/jcs.01517

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Protein kinase B phosphorylation of PIKfyve regulates the trafficking of GLUT4 vesicles

Daniel C. Berwick^1,*,, Ghislaine C. Dell^1,, Gavin I. Welsh^1,, Kate J. Heesom¹, Ingeborg Hers¹, Laura M. Fletcher¹, Frank T. Cooke² and Jeremy M. Tavaré^1,

¹ Department of Biochemistry, School of Medical Sciences, University of Bristol, University Walk, Bristol, BS8 1TD, UK
² Department of Biochemistry and Molecular Biology, University College London, Gower Street, London, W1E 6BT, UK

Author for correspondence (e-mail: j.tavare{at}bris.ac.uk)

Accepted 31 August 2004

Insulin-stimulated glucose uptake involves the recruitment of the glucose transporter 4 isoform (GLUT4) from an intracellular location to the plasma membrane of fat and muscle cells. Although the activation of the PI3-kinase/protein kinase B (PKB) pathway is central to this effect of insulin, the key substrates for PKB that are involved require identification. Here we report that serine318 on the FYVE domain-containing PtdIns(3)P 5-kinase (PIKfyve) is a novel substrate for PKB, and show that phosphorylation stimulates the PtdIns(3)P 5-kinase activity of the enzyme. We also demonstrate that PIKfyve is phosphorylated on serine318 in intact cells in response to insulin, in a PI3-kinase-dependent manner, and that PIKfyve colocalises with a highly motile subpopulation of insulin-regulated aminopeptidase (IRAP)/GLUT4 vesicles. Finally, we demonstrate that overexpression of a PIKfyve[S318A] mutant in 3T3-L1 adipocytes enhances insulin-stimulated IRAP/GLUT4 vesicle translocation to the plasma membrane suggesting a role for PKB-dependent phosphorylation of PIKfyve in insulin-regulated IRAP/GLUT4 trafficking. The phosphorylation and activation of PIKfyve by PKB provides a novel signalling paradigm that may link plasma membrane-localised PtdIns(3,4,5)P₃ signals via a protein kinase cascade to regulated PtdIns(3,5)P₂ production, and thereby to the control of trafficking of other membrane cargos.

Key words: Insulin, Signalling, Glucose transport, Protein kinase B, Phosphoinositide

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