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Cell Metab. 2011 Sep 7;14(3):378-89. doi: 10.1016/j.cmet.2011.06.015.

C2 domain-containing phosphoprotein CDP138 regulates GLUT4 insertion into the plasma membrane.

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  • 1Metabolic Signaling and Disease Program, Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, FL 32827, USA.

Abstract

The protein kinase B(β) (Akt2) pathway is known to mediate insulin-stimulated glucose transport through increasing glucose transporter GLUT4 translocation from intracellular stores to the plasma membrane (PM). Combining quantitative phosphoproteomics with RNAi-based functional analyses, we show that a previously uncharacterized 138 kDa C2 domain-containing phosphoprotein (CDP138) is a substrate for Akt2, and is required for optimal insulin-stimulated glucose transport, GLUT4 translocation, and fusion of GLUT4 vesicles with the PM in live adipocytes. The purified C2 domain is capable of binding Ca(2+) and lipid membranes. CDP138 mutants lacking the Ca(2+)-binding sites in the C2 domain or Akt2 phosphorylation site S197 inhibit insulin-stimulated GLUT4 insertion into the PM, a rate-limiting step of GLUT4 translocation. Interestingly, CDP138 is dynamically associated with the PM and GLUT4-containing vesicles in response to insulin stimulation. Together, these results suggest that CDP138 is a key molecule linking the Akt2 pathway to the regulation of GLUT4 vesicle-PM fusion.

Copyright © 2011 Elsevier Inc. All rights reserved.

PMID:
21907143
[PubMed - indexed for MEDLINE]
PMCID:
PMC3172579
Free PMC Article

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