Cdk5-mediated regulation of the PIKE-A-Akt pathway and glioblastoma cell invasion
Cdk5-mediated regulation of the PIKE-A-Akt pathway and glioblastoma cell invasion
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DOI：
10.1073/pnas.0712306105
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发表时间：
2008-05-27
影响因子：
11.1
通讯作者：
Mao, Zixu
中科院分区：
文献类型：
--
作者：
Liu, Ren;Tian, Bo;Mao, Zixu
磷脂酰肌醇3-激酶增强子亚型A（PIKE-A）是一种新发现的与癌细胞生长有关的原癌因子。PIKE-A活性是如何响应生长信号而调节的，目前还知之甚少。在这里，我们证明了细胞周期蛋白依赖性激酶5（Cdk 5），一种已知主要在有丝分裂后神经元中起作用的蛋白质，直接磷酸化PIKE-A在其GT3结构域中的Ser-279在胶质母细胞瘤细胞中。该磷酸化事件刺激PIKE-A GT3活性及其下游效应物Akt的活性。生长信号激活Cdk 5并导致细胞核中磷酸化PIKE-A的Cdk 5依赖性积累和Akt的激活。此外，PIKE-A磷酸化和Cdk 5在人胶质母细胞瘤标本中增加。Cdk 5对PIKE-A的磷酸化介导生长因子诱导的人胶质母细胞瘤细胞迁移和侵袭总之，这些发现将PIKE确定为癌细胞中的第一个Cdk 5靶点，揭示了一种以前未描述的调节机制，该机制介导生长信号诱导的PIKE-A/Akt活化和肿瘤侵袭。
Isoform A of phosphatidylinositol 3-kinase enhancer (PIKE-A) is a newly identified prooncogenic factor that has been implicated in cancer cell growth. How PIKE-A activity is regulated in response to growth signal is poorly understood. Here, we demonstrate that cyclin dependent kinase 5 (Cdk5), a protein known to function mainly in postmitotic neurons, directly phosphorylates PIKE-A at Ser-279 in its GTPase domain in glioblastoma cells. This phosphorylation event stimulates PIKE-A GTPase activity and the activity of its downstream effector Akt. Growth signal activates Cdk5 and results in a Cdk5-dependent accumulation of phosphorylated PIKE-A and activation of Akt in the nucleus. Furthermore, PIKE-A phosphorylation and Cdk5 are increased in human glioblastoma specimens. Phosphorylation of PIKE-A by Cdk5 mediates growth factor-induced migration and invasion of human glioblastoma cells. Together, these findings identify PIKE as the first Cdk5 target in cancer cells, revealing a previously undescribed regulatory mechanism that mediates growth signal-induced activation of PIKE-A/Akt and tumor invasion.