Carboxy-terminal modulator protein induces Akt phosphorylation and activation, thereby enhancing antiapoptotic, glycogen synthetic, and glucose uptake pathways
Carboxy-terminal modulator protein induces Akt phosphorylation and activation, thereby enhancing antiapoptotic, glycogen synthetic, and glucose uptake pathways
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DOI：
10.1152/ajpcell.00570.2006
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发表时间：
2007-11-01
影响因子：
5.5
通讯作者：
Asano, Tomoichiro
中科院分区：
文献类型：
--
作者：
Ono, Hiraku;Sakoda, Hideyuki;Asano, Tomoichiro
羧基末端调节蛋白（carboxy-terminal modulator protein，CTMP）被鉴定为与Akt的羧基末端结合并抑制Akt的磷酸化和活化。与先前的研究相反，我们发现CTMP过表达显著增强Akt在Thr（308）和Ser（473）的磷酸化以及Akt的激酶活性，而磷脂酰肌醇3-激酶（PI3-激酶）活性不受影响。Akt向膜组分的转运也显著增加，对CTMP的过表达作出反应，而Akt的整个细胞含量没有变化。此外，GSK-3 β和Foxo 1（Akt的已知底物）的磷酸化通过CTMP过表达而增加。另一方面，用小干扰RNA抑制CTMP部分但显著地减弱了Akt磷酸化。据报道，由Akt激活介导的细胞活性也通过CTMP过表达而增强。UV-B诱导的HeLa细胞凋亡不仅被Akt活性突变体（myr-Akt）的过表达逆转，而且被CTMP的过表达逆转。在3T3-L1脂肪细胞中，myr-Akt或CTMP的过表达也诱导葡萄糖转运活性和糖原合成的增加。考虑到这些结果，可以得出结论，CTMP诱导Akt易位到膜，从而增加Akt磷酸化的水平。因此，CTMP增强主要由PI3-激酶/Akt途径介导的各种细胞活性。
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 Thr(308) and Ser(473) 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-3 beta 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.