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。
Activation of PI3K/Akt pathway by CD133-p85 interaction promotes tumorigenic capacity of glioma stem cells.
机构信息
Key Laboratory of Glycoconjuates Research, Ministry of Public Health, Department of Biochemistry and Molecular Biology, Shanghai Medical College of Fudan University, Shanghai 200032, People's Republic of China.
出版信息
Proc Natl Acad Sci U S A. 2013 Apr 23;110(17):6829-34. doi: 10.1073/pnas.1217002110. Epub 2013 Apr 8.
Abstract
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.
摘要
已知的正常和癌症干细胞标志物 CD133 的生物学意义仍不明确。我们现在证明，CD133 胞质 C 端尾部酪氨酸-828 残基的磷酸化介导 CD133 与磷酸肌醇 3-激酶（PI3K）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）中 PI3K/蛋白激酶 B（Akt）通路的优先激活，与匹配的非干细胞相比。CD133 敲低强烈抑制 PI3K/Akt 通路的活性，同时伴随 GSC 自我更新和致瘤性的降低。WT CD133 的表达可以完全挽救 CD133 敲低的抑制作用，但 Y828F 突变体（p85 结合缺陷）则不行。对胶质瘤样本的分析表明，CD133 Y828 磷酸化水平与组织病理学分级相关，并与 Akt 激活重叠。我们的结果确定了 CD133/PI3K/Akt 信号轴，探索了 CD133 在胶质瘤干细胞行为中的基本作用。
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