Cellular energy stress induces AMPK-mediated regulation of glioblastoma cell proliferation by PIKE-A phosphorylation
Cellular energy stress induces AMPK-mediated regulation of glioblastoma cell proliferation by PIKE-A phosphorylation
复制标题
细胞能量应激通过 PIKE-A 磷酸化诱导 AMPK 介导的胶质母细胞瘤细胞增殖调节
DOI：
10.1038/s41419-019-1452-1
复制
发表时间：
2019-03-04
影响因子：
9
通讯作者：
Ye, Keqiang
中科院分区：
文献类型：
--
作者：
Zhang, Shuai;Sheng, Hao;Ye, Keqiang
肌醇磷脂3-激酶增强子激活蛋白Akt(Pike-A)是一种与Akt结合并增强Akt活性的致癌因子，对癌细胞的生存和生长起着至关重要的作用。然而，对Pike-A在能量/营养缺乏条件下的生理功能知之甚少。AMP激活的蛋白激酶(AMPK)是一种进化上保守的丝氨酸/苏氨酸激酶，是能量平衡的主要调节因子，在代谢紊乱和癌症中起着关键作用。在本研究中，我们发现细胞能量应激通过激活AMPK来诱导Pike-A的磷酸化，从而阻止其致癌作用。此外，AMPK直接磷酸化Pike-A Ser-351和Ser-377，与14-3-3β相互作用，进而刺激Pike-A的核转位。核的Pike-A与CDK4结合，然后破坏CDK4-CyClinD1复合体，抑制Rb通路，导致癌细胞周期停滞。我们的数据揭示了AMPK介导的Pike-A对细胞能量状态的磷酸化反应的分子机制和功能意义。
Phosphoinositide 3-kinase enhancer-activating Akt (PIKE-A), which associates with and potentiates Akt activity, is a pro-oncogenic factor that play vital role in cancer cell survival and growth. However, PIKE-A physiological functions under energy/nutrient deficiency are poorly understood. The AMP-activated protein kinase (AMPK) is an evolutionarily conserved serine/threonine kinase that is a principal regulator of energy homeostasis and has a critical role in metabolic disorders and cancers. In this present study, we show that cellular energy stress induces PIKE-A phosphorylation mediated by AMPK activation, thereby preventing its carcinogenic action. Moreover, AMPK directly phosphorylates PIKE-A Ser-351 and Ser-377, which become accessible for the interaction with 14-3-3β, and in turn stimulates nuclear translocation of PIKE-A. Nuclear PIKE-A associates with CDK4 and then disrupts CDK4-cyclinD1 complex and inhibits the Rb pathway, resulting in cancer cell cycle arrest. Our data uncover a molecular mechanism and functional significance of PIKE-A phosphorylation response to cellular energy status mediated by AMPK.