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首页> 外文期刊>Cellular Signalling >Crosstalk between VEGFR2 and muscarinic receptors regulates the mTOR pathway in serum starved SK-N-SH human neuroblastoma cells
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Crosstalk between VEGFR2 and muscarinic receptors regulates the mTOR pathway in serum starved SK-N-SH human neuroblastoma cells

机译：VEGFR2与毒蕈碱受体之间的串扰调节血清饥饿的SK-N-SH人成神经细胞瘤细胞中的mTOR通路

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Muscarinic acetylcholine receptors (mAchRs) are guanosine nucleotide-binding protein (G protein) coupled receptors that crosstalk with receptor tyrosine kinases (RTKs) to signal mitogenic pathways. In particular, mAchRs are known to couple with RTKs for several growth factors to activate the mammalian target of rapamycin (mTOR)/Akt pathway, a regulator of protein synthesis. The RTK for the vascular endothelial growth factor (VEGF), VEGFR2, can signal protein synthesis but whether it cooperates with mAchRs to mediate mTOR activation has not been demonstrated. Using serum starved SK-N-SH neuroblastoma cells, we show that the muscarinic receptor agonists carbachol and pilocarpine enhance the activation of the mTOR substrate p70 S6 Kinase (S6K) and its target ribosomal protein S6 (S6) in a VEGFR2 dependent manner. Treatments with carbachol increased VEGFR2 phosphorylation, suggesting that mAchRs stimulate VEGFR2 transactivation to enhance mTOR signaling. Inhibitor studies revealed that phosphatidylinositol 3 kinase resides upstream from S6K, S6 and Akt phosphorylation while protein kinase C (PKC) functions in an opposing fashion by positively regulating S6K and S6 phosphorylation and suppressing Akt activation. Treatments with the phosphatase inhibitors sodium orthovanadate and okadaic acid increase S6, Akt and to a lesser extent S6K phosphorylation, indicating that tyrosine and serine/threonine dephosphorylation also regulates their activity. However, okadaic acid elicited a far greater increase in phosphorylation, implicating phosphatase 2A as a critical determinant of their function. Finally, pilocarpine but not carbachol induced a time and dose dependent cell death that was associated with caspase activation and oxidative stress but independent of S6K and S6 activation through VEGFR2. Accordingly, our findings suggest that mAchRs crosstalk with VEGFR2 to enhance mTOR activity but signal divergent effects on survival through alternate mechanisms.
机译：毒蕈碱型乙酰胆碱受体（mAchRs）是鸟嘌呤核苷酸结合蛋白（G蛋白）偶联的受体，与受体酪氨酸激酶（RTKs）串扰以发出有丝分裂途径。特别地，已知mAchRs与RTKs结合几种生长因子，以激活雷帕霉素（mTOR）/ Akt途径（蛋白质合成的调节剂）的哺乳动物靶标。血管内皮生长因子（VEGF）VEGFR2的RTK可以发出信号，指示蛋白质合成，但尚未证明它是否与mAchRs协同介导mTOR活化。使用血清饥饿的SK-N-SH神经母细胞瘤细胞，我们显示毒蕈碱受体激动剂卡巴胆碱和毛果芸香碱以VEGFR2依赖性方式增强mTOR底物p70 S6激酶（S6K）及其靶核糖体蛋白S6（S6）的激活。卡巴胆碱的治疗可增加VEGFR2的磷酸化，提示mAchRs刺激VEGFR2反式激活以增强mTOR信号传导。抑制剂研究表明，磷脂酰肌醇3激酶位于S6K，S6和Akt磷酸化的上游，而蛋白激酶C（PKC）通过正向调节S6K和S6磷酸化并抑制Akt活化以相反的方式发挥作用。用磷酸酶抑制剂原钒酸钠和冈田酸处理可增加S6，Akt并在较小程度上增加S6K磷酸化，表明酪氨酸和丝氨酸/苏氨酸的去磷酸化也调节了它们的活性。然而，冈田酸引起磷酸化的增加更多，暗示磷酸酶2A是其功能的关键决定因素。最后，毛果芸香碱而不是卡巴胆碱诱导时间和剂量依赖性细胞死亡，这与胱天蛋白酶激活和氧化应激有关，但与通过VEGFR2引起的S6K和S6激活无关。因此，我们的发现表明，mAchRs与VEGFR2发生串扰可增强mTOR活性，但通过替代机制对生存信号发散作用。

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