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PROTEIN AND VESICLE TRAFFICKING, CYTOSKELETON

Carboxy-terminal modulator protein induces Akt phosphorylation and activation, thereby enhancing antiapoptotic, glycogen synthetic, and glucose uptake pathways

¹Department of Endocrinology and Metabolism, Institute for Adult Disease, Asahi Life Foundation, Chiyoda-ku, Tokyo; ²Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo; ³Division of Advanced Therapeutics for Metabolic Diseases, Department of Translational Research, Tohoku University, Graduate School of Medicine, Aoba-ku, Sendai, Miyagi; ⁴Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo; and ⁵Department of Medical Science, Graduate School of Medicine, University of Hiroshima, Minami-ku, Hiroshima City, Hiroshima, Japan

Submitted 9 November 2006 ; accepted in final form 3 July 2007

Carboxy-terminal modulator protein (CTMP) was identified as binding to the carboxy terminus of Akt and inhibiting the phosphorylation and activation of Akt. In contrast to a previous study, we found CTMP overexpression to significantly enhance Akt phosphorylation at both Thr³⁰⁸ and Ser⁴⁷³ as well as the kinase activity of Akt, while phosphatidylinositol 3-kinase (PI3-kinase) activity was unaffected. Translocation of Akt to the membrane fraction was also markedly increased in response to overexpression of CTMP, with no change in the whole cellular content of Akt. Furthermore, the phosphorylations of GSK-3β and Foxo1, well-known substrates of Akt, were increased by CTMP overexpression. On the other hand, suppression of CTMP with small interfering RNA partially but significantly attenuated this Akt phosphorylation. The cellular activities reportedly mediated by Akt activation were also enhanced by CTMP overexpression. UV-B-induced apoptosis of HeLa cells was significantly reversed not only by overexpression of the active mutant of Akt (myr-Akt) but also by that of CTMP. Increases in glucose transport activity and glycogen synthesis were also induced by overexpression of either myr-Akt or CTMP in 3T3-L1 adipocytes. Taking these results into consideration, it can be concluded that CTMP induces translocation of Akt to the membrane and thereby increases the level of Akt phosphorylation. As a result, CTMP enhances various cellular activities that are principally mediated by the PI3-kinase/Akt pathway.

phosphatidylinositol 3-kinase

This article has been cited by other articles:

				T. F. Franke Akt-interacting proteins: attractive opposites. Focus on "Carboxy-terminal modulator protein induces Akt phosphorylation and activation, thereby enhancing antiapoptotic, glycogen synthetic, and glucose uptake pathways" Am J Physiol Cell Physiol, December 1, 2007; 293(6): C1768 - C1770. [Full Text] [PDF]