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

Berwick, Daniel C.; Dell, Ghislaine C.; Welsh, Gavin I.; Heesom, Kate J.; Hers, Ingeborg; Fletcher, Laura M.; Cooke, Frank T. and Tavaré, Jeremy M. (2004). Protein kinase B phosphorylation of PIKfyve regulates the trafficking of GLUT4 vesicles. Journal of cell science, 117 pp. 5985–5993.

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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.

Item Type: Journal Item
Copyright Holders: 2004 The Company of Biologists Limited
ISSN: 0021-9533
Project Funding Details:
Funded Project NameProject IDFunding Body
Postgraduate ScholarshipNot SetUniversity of Bristol
Keywords: Insulin; signalling; glucose transport; protein kinase B; Phosphoinositide
Academic Unit/School: Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences
Faculty of Science, Technology, Engineering and Mathematics (STEM)
Item ID: 44270
Depositing User: Daniel Berwick
Date Deposited: 30 Sep 2015 13:53
Last Modified: 20 May 2019 10:10
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