WNK1 Promotes PIP2 Synthesis to Coordinate Growth Factor and GPCR-Gq Signaling
WNK1 Promotes PIP2 Synthesis to Coordinate Growth Factor and GPCR-Gq Signaling
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DOI：
10.1016/j.cub.2011.11.002
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发表时间：
2011-12-06
期刊：
影响因子：
9.2
通讯作者：
Huang, Chou-Long
中科院分区：
文献类型：
--
作者：
An, Sung-Wan;Cha, Seung-Kuy;Huang, Chou-Long
背景：PLC-β信号通常被认为是由G蛋白和Ca 2+介导的变构激活。虽然磷脂酰肌醇-4，5-二磷酸（PIP 2）底物的可用性在某些情况下是有限的，但其产生尚未显示出作为信号传导机制被独立调节。已知WNK 1蛋白激酶调节离子稳态并在基因突变导致表达增加时引起高血压。然而，它的信号功能仍然在很大程度上hailing.Results：使用二酰基甘油刺激的TRPC 6和三磷酸肌醇介导的Ca 2+瞬变作为细胞生物传感器，我们表明，WNK 1刺激PLC-β信号在细胞中通过促进PIP 2的合成，通过刺激磷脂酰肌醇4-激酶III α。不需要WNK 1激酶活性。WNK 1和G alpha（q）对PLC-β的刺激是协同作用的; WNK 1活性对于G（q）偶联受体调节PLC-β信号传导至关重要，并且来自G（q）的基础输入对于WNK 1通过PLC-β信号传导是必需的。WNK 1进一步放大PLC-β信号时，它是由Akt激酶在响应胰岛素样growthfactor.Conclusions磷酸化：WNK 1是一种新的调节PLC-β，通过控制底物的可用性。WNK 1因此协调G蛋白和Akt激酶通路之间的信号传导。由于PIP 2本身是一种信号分子，WNK 1对PIP 2合成的调节也允许细胞启动PLC信号传导，同时独立控制PIP 2对其他靶点的影响。这些发现描述了Akt激活生长因子的新信号传导途径，G蛋白-生长因子串扰的机制，以及独立控制PLC信号传导和PIP 2可用性的方法。
Background: PLC-beta signaling is generally thought to be mediated by allosteric activation by G proteins and Ca2+. Although availability of the phosphatidylinositol-4,5-biphosphate (PIP2) substrate is limiting in some cases, its production has not been shown to be independently regulated as a signaling mechanism. WNK1 protein kinase is known to regulate ion homeostasis and cause hypertension when expression is increased by gene mutations. However, its signaling functions remain largely elusive.Results: Using diacylglycerol-stimulated TRPC6 and inositol trisphosphate-mediated Ca2+ transients as cellular biosensors, we show that WNK1 stimulates PLC-beta signaling in cells by promoting the synthesis of PIP2 via stimulation of phosphatidylinositol 4-kinase III alpha. WNK1 kinase activity is not required. Stimulation of PLC-beta by WNK1 and by G alpha(q) are synergistic; WNK1 activity is essential for regulation of PLC-beta signaling by G(q)-coupled receptors, and basal input from G(q) is necessary for WNK1 signaling via PLC-beta. WNK1 further amplifies PLC-beta signaling when it is phosphorylated by Akt kinase in response to insulin-like growth factor.Conclusions: WNK1 is a novel regulator of PLC-beta that acts by controlling substrate availability. WNK1 thereby coordinates signaling between G protein and Akt kinase pathways. Because PIP2 is itself a signaling molecule, regulation of PIP2 synthesis by WNK1 also allows the cell to initiate PLC signaling while independently controlling the effects of PIP2 on other targets. These findings describe a new signaling pathway for Akt-activating growth factors, a mechanism for G protein-growth factor crosstalk, and a means to independently control PLC signaling and PIP2 availability.