A novel leptin signalling pathway via PTEN inhibition in hypothalamic cell lines and pancreatic β-cells
A novel leptin signalling pathway via PTEN inhibition in hypothalamic cell lines and pancreatic β-cells
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DOI：
10.1038/sj.emboj.7601118
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发表时间：
2006-06-07
期刊：
影响因子：
11.4
通讯作者：
Ashford, Michael L. J.
中科院分区：
文献类型：
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作者：
Ning, Ke;Miller, Lisa C.;Ashford, Michael L. J.
在肥胖和糖尿病中，下丘脑神经元感知和监测瘦素和胰岛素水平变化的能力受到损害。这两种激素的作用需要通过PI 3-激酶途径的细胞内信号传导，该途径被磷酸酶PTEN抑制。我们发现，瘦素刺激的小鼠下丘脑细胞中的F-肌动蛋白解聚被PTEN抑制，这是一个涉及其脂质和蛋白磷酸酶活性的独立效应的过程。可能介导这种F-肌动蛋白解聚，瘦素，而不是胰岛素，刺激磷酸化的PTEN在CK 2依赖的方式，并抑制其磷酸酶活性。类似地，瘦素引起的小鼠胰腺b细胞超极化也需要同时产生PtdIns（3，4，5）P-3和肌动蛋白解聚，并且可以通过需要PTEN的脂质和蛋白磷酸酶活性的机制来抑制。这些结果证明了PTEN在瘦素信号传导中的关键作用，并表明瘦素和胰岛素可以产生PI 3 K依赖性差异细胞输出的机制。
In obesity and diabetes, the ability of hypothalamic neurons to sense and transduce changes in leptin and insulin levels is compromised. The effects of both hormones require intracellular signalling via the PI3-kinase pathway, which is inhibited by the phosphatase PTEN. We show that leptin- stimulated F-actin depolymerization in mouse hypothalamic cells is inhibited by PTEN, a process involving independent effects of both its lipid and protein phosphatase activities. Potentially mediating this F-actin depolymerization, leptin, but not insulin, stimulated the phosphorylation of PTEN in a CK2 dependent manner, and inhibited its phosphatase activity. Similarly, hyperpolarization of mouse pancreatic b-cells by leptin also requires coincident PtdIns(3,4,5) P-3 generation and actin depolymerization, and could be inhibited by mechanisms requiring both the lipid and protein phosphatase activities of PTEN. These results demonstrate a critical role for PTEN in leptin signalling and indicate a mechanism by which leptin and insulin can produce PI3K dependent differential cellular outputs.