Article

C2 Domain-Containing Phosphoprotein CDP138 Regulates GLUT4 Insertion into the Plasma Membrane

Metabolic Signaling and Disease Program, Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, FL 32827, USA.
Cell metabolism (Impact Factor: 16.75). 09/2011; 14(3):378-89. DOI: 10.1016/j.cmet.2011.06.015
Source: PubMed

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.

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    • "Based on those findings, it became important to assess the potential contribution of Ca 2+ to downstream insulin action. Indeed, there are reports that GLUT4 exocytosis requires intracellular Ca 2+ in adipocytes, allowing activation of Akt (Whitehead et al., 2001) and CDP138, a Ca 2+ -dependent protein downstream of Akt (Xie et al., 2011). In skeletal muscle, however, direct evidence showing intracellular Ca 2+ -dependent GLUT4 translocation was missing though suggested (Lanner et al., 2006; Wijesekara et al., 2006), and localized, sub-membrane changes in Ca 2+ levels have been reported in response to the hormone (Bruton et al., 1999). "
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    Journal of Cell Science 02/2014; 127(9). DOI:10.1242/jcs.138982 · 5.33 Impact Factor
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    • "Indeed, there are reports that GLUT4 exocytosis requires intracellular Ca 2+ in adipocytes, allowing activation of Akt (Whitehead et al., 2001) and CDP138, a Ca 2+ -dependent protein downstream of Akt (Xie et al., 2011). In skeletal muscle, however, direct evidence showing intracellular Ca 2+ -dependent GLUT4 translocation was missing, although results have suggested that it occurs (Lanner et al., 2006; Wijesekara et al., 2006), and localized, sub-membrane changes in Ca 2+ levels have been reported in response to the hormone (Bruton et al., 1999). "
    Biophysical Journal 01/2013; 104(2):617-. DOI:10.1016/j.bpj.2012.11.3414 · 3.97 Impact Factor
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    • "The exercise-induced increase in AS160 phosphorylation in the epitrochlearis was not found with all insulin doses, suggesting that other mechanisms might also contribute to the elevated glucose uptake that was found with each insulin concentration. In this context, it would be valuable to study the effects of exercise by old rats on other Akt substrates that have been implicated as regulators of GLUT4 translocation, e.g., TBC1D1, myosin 5A, and CDP138 (Roach et al. 2007; Yoshizaki et al. 2007; Xie et al. 2011). Finally, it would also be useful to use genetic or chemical approaches to modulate Akt and/or AS160 phosphorylation in muscles from old animals to test the role of these signaling proteins in the improved insulinstimulated glucose uptake after exercise. "
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