Activation of PI3K/Akt pathway by CD133-p85 interaction promotes tumorigenic capacity of glioma stem cells
Activation of PI3K/Akt pathway by CD133-p85 interaction promotes tumorigenic capacity of glioma stem cells
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CD133-p85相互作用激活PI3K/Akt通路促进神经胶质瘤干细胞的致瘤能力
DOI：
10.1073/pnas.1217002110
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发表时间：
2013-04-23
影响因子：
11.1
通讯作者：
Jiang, Jianhai
中科院分区：
文献类型：
--
作者：
Wei, Yuanyan;Jiang, Yizhou;Jiang, Jianhai
已知的正常和癌症干细胞标志物CD 133的生物学意义仍然难以捉摸。我们现在证明，CD 133 C端胞质结构域中的酪氨酸-828残基的磷酸化介导了CD 133与磷脂酰肌醇3-激酶（PI 3 K）85 kDa调节亚基（p85）之间的直接相互作用，导致胶质瘤干细胞（GSC）相对于匹配的非干细胞优先激活PI 3 K/蛋白激酶B（Akt）通路。CD 133基因敲低可有效抑制PI 3 K/Akt通路的活性，同时降低GSC的自我更新和致瘤性。CD 133敲低的抑制作用可以通过WT CD 133的表达而被完全拯救，但不能通过其p85结合缺陷型Y828 F突变体。对胶质瘤样本的分析显示，CD 133 Y828磷酸化水平与组织病理学分级相关，并与Akt活化重叠。我们的研究结果确定了CD 133/PI 3 K/Akt信号转导轴，探讨了CD 133在胶质瘤干细胞行为中的基本作用。
The biological significance of a known normal and cancer stem cell marker CD133 remains elusive. We now demonstrate that the phosphorylation of tyrosine-828 residue in CD133 C-terminal cytoplasmic domain mediates direct interaction between CD133 and phosphoinositide 3-kinase (PI3K) 85 kDa regulatory subunit (p85), resulting in preferential activation of PI3K/protein kinase B (Akt) pathway in glioma stem cell (GSC) relative to matched nonstem cell. CD133 knockdown potently inhibits the activity of PI3K/Akt pathway with an accompanying reduction in the self-renewal and tumorigenicity of GSC. The inhibitory effects of CD133 knockdown could be completely rescued by expression of WT CD133, but not its p85-binding deficient Y828F mutant. Analysis of glioma samples reveals that CD133 Y828 phosphorylation level is correlated with histopathological grade and overlaps with Akt activation. Our results identify the CD133/PI3K/Akt signaling axis, exploring the fundamental role of CD133 in glioma stem cell behavior.