Emerging role for AS160/TBC1D4 and TBC1D1 in the regulation of GLUT4 traffic

Emerging role for AS160/TBC1D4 and TBC1D1 in the regulation of GLUT4 traffic Vesicular traffic of the glucose transporter GLUT4 occurs in response to insulin, muscle contraction, and metabolic stimuli that lead to changes in the energy status of the cell. These stimuli are associated with linked kinase cascades that lead to changes in glucose uptake that meet the energy challenges imposed on the highly regulated cell types in insulin-responsive tissues. The need to mechanistically link these kinase-associated stimuli to identifiable intermediates in vesicular traffic has long been known but has been difficult to fulfill. The Rab-GTPase-activating proteins AS160 and TBC1D1 have now emerged as strong candidates to fill this void. Here we review the initial discovery of these proteins as phosphorylated substrates for Akt and the more recent emerging data that indicate that these proteins are substrates for additional kinases that are downstream of contraction and energy status signaling. The mechanism of coupling these phosphorylated proteins to vesicle traffic appears to be dependent on linking to small GTPase of the Rab family. We examine the current state of a hypothesis that suggests that phosphorylation of the Rab-GTPase-activating proteins leads to increased GTP loading of Rab proteins on GLUT4 vesicles and subsequently to increased interaction with Rab effectors that control GLUT4 vesicle translocation. glucose transport; insulin signaling; glucose transporter 4; type 2 diabetes; Akt Address for reprint requests and other correspondence: K. Sakamoto, MRC Protein Phosphorylation Unit, College of Life Sciences, Univ. of Dundee, Dow St., Dundee, DD1 5EH, UK (e-mail: k.sakamoto@dundee.ac.uk ) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png AJP - Endocrinology and Metabolism The American Physiological Society

Emerging role for AS160/TBC1D4 and TBC1D1 in the regulation of GLUT4 traffic

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Publisher
The American Physiological Society
Copyright
Copyright © 2011 the American Physiological Society
ISSN
0193-1849
eISSN
1522-1555
D.O.I.
10.1152/ajpendo.90331.2008
Publisher site
See Article on Publisher Site

Abstract

Vesicular traffic of the glucose transporter GLUT4 occurs in response to insulin, muscle contraction, and metabolic stimuli that lead to changes in the energy status of the cell. These stimuli are associated with linked kinase cascades that lead to changes in glucose uptake that meet the energy challenges imposed on the highly regulated cell types in insulin-responsive tissues. The need to mechanistically link these kinase-associated stimuli to identifiable intermediates in vesicular traffic has long been known but has been difficult to fulfill. The Rab-GTPase-activating proteins AS160 and TBC1D1 have now emerged as strong candidates to fill this void. Here we review the initial discovery of these proteins as phosphorylated substrates for Akt and the more recent emerging data that indicate that these proteins are substrates for additional kinases that are downstream of contraction and energy status signaling. The mechanism of coupling these phosphorylated proteins to vesicle traffic appears to be dependent on linking to small GTPase of the Rab family. We examine the current state of a hypothesis that suggests that phosphorylation of the Rab-GTPase-activating proteins leads to increased GTP loading of Rab proteins on GLUT4 vesicles and subsequently to increased interaction with Rab effectors that control GLUT4 vesicle translocation. glucose transport; insulin signaling; glucose transporter 4; type 2 diabetes; Akt Address for reprint requests and other correspondence: K. Sakamoto, MRC Protein Phosphorylation Unit, College of Life Sciences, Univ. of Dundee, Dow St., Dundee, DD1 5EH, UK (e-mail: k.sakamoto@dundee.ac.uk )

Journal

AJP - Endocrinology and MetabolismThe American Physiological Society

Published: Jul 1, 2008

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