Cellular Notch responsiveness is defined by phosphoinositide 3-kinase-dependent signals.
Cellular Notch responsiveness is defined by phosphoinositide 3-kinase-dependent signals.
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DOI：
10.1186/1471-2121-7-10
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发表时间：
2006-02-28
期刊：
影响因子：
--
通讯作者：
Hardingham GE
中科院分区：
文献类型：
--
作者：
McKenzie G;Ward G;Stallwood Y;Briend E;Papadia S;Lennard A;Turner M;Champion B;Hardingham GE
Notch在控制细胞命运、分化和发育中起着广泛的作用。PI 3 K-Akt通路是一种类似的保守信号传导通路，其调节诸如分化、增殖和存活的过程。Notch和PI 3 K信号转导被破坏的小鼠在造血细胞发育期间显示出表型相似性，表明这些途径之间存在功能性相互作用。我们表明，细胞对Notch信号的反应性取决于细胞中PI 3 K-Akt通路的活性，这些细胞如CHO细胞、原代T细胞和海马神经元。在CHO细胞中（通过胰岛素途径）、在T细胞中（通过TCR活化）或在神经元中（通过TrKB活化）诱导内源性PI 3 K-Akt途径增强Notch依赖性应答。我们认为PI 3 K-Akt通路主要通过抑制GSK 3-β对Notch产生影响，GSK 3-β是一种已知的磷酸化和调节Notch信号的激酶。PI 3 K-Akt途径充当Notch信号应答的“增益控制”。由于细胞内Notch的生理水平通常较低，因此与PI 3 K活化的一致性对于诱导Notch依赖性应答可能是至关重要的。
Notch plays a wide-ranging role in controlling cell fate, differentiation and development. The PI3K-Akt pathway is a similarly conserved signalling pathway which regulates processes such as differentiation, proliferation and survival. Mice with disrupted Notch and PI3K signalling show phenotypic similarities during haematopoietic cell development, suggesting functional interaction between these pathways. We show that cellular responsiveness to Notch signals depends on the activity of the PI3K-Akt pathway in cells as diverse as CHO cells, primary T-cells and hippocampal neurons. Induction of the endogenous PI3K-Akt pathway in CHO cells (by the insulin pathway), in T-cells (via TCR activation) or in neurons (via TrKB activation) potentiates Notch-dependent responses. We propose that the PI3K-Akt pathway exerts its influence on Notch primarily via inhibition of GSK3-beta, a kinase known to phosphorylate and regulate Notch signals. The PI3K-Akt pathway acts as a "gain control" for Notch signal responses. Since physiological levels of intracellular Notch are often low, coincidence with PI3K-activation may be crucial for induction of Notch-dependent responses.
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