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Am J Physiol Cell Physiol (July 5, 2007). doi:10.1152/ajpcell.00570.2006
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Submitted on November 9, 2006
Accepted on July 3, 2007

CARBOXYL-TERMINAL MODULATOR PROTEIN (CTMP) INDUCES AKT PHOSPHORYLATION AND ACTIVATION, THEREBY ENHANCING ANTI-APOPTOTIC, GLYCOGEN SYNTHETIC AND GLUCOSE UPTAKE PATHWAYS

Hiraku Ono1, Hideyuki Sakoda2, Midori Fujishiro2, Motonobu Anai1, Akifumi Kushiyama2, Yasushi Fukushima2, Hideki Katagiri3, Takehide Ogihara3, Yoshitomo Oka3, Hideaki Kamata4, Nanao Horike5, Yasunobu Uchijima5, Hiroki Kurihara5, and Tomoichiro Asano6*

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

* To whom correspondence should be addressed. E-mail: asano-tky{at}umin.ac.jp.

Carboxyl-terminal modulator protein (CTMP) was identified as binding to the carboxyl-terminus of Akt and inhibiting the phosphorylation and activation of Akt. In contrast to a previous study, we found CTMP overexpression to markedly enhance Akt phosphorylation at both Thr308 and Ser473 as well as the kinase activity of Akt, while PI 3-kinase activity was unaffected. Translocation of Akt to the membrane fraction was also markedly increased in response to overexpressing CTMP with no change in the whole cellular content of Akt. Furthermore, the phosphorylations of GSK-3{beta} and Foxo1, well-known substrates of Akt, were increased by CTMP overexpression. On the other hand, suppression of CTMP using siRNA 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 by overexpression of not only 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 overexpressing 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 which are principally mediated by the PI 3-kinase/Akt pathway.




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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.
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