上腺素通过Hippo激酶抑制PI3Kα
Ting-Yu Lin1, Shakti Ramsamooj2, Tiffany Perrier2
1Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA; Weill Cornell Graduate School of Medical Sciences, New York, NY 10021, USA.
希波基纳斯通过酸化T1061抑制酸3-基纳斯p110α活性,影响胰岛素信号传递和葡萄糖代谢. 这一发现揭示了一种新的抑制途径,将上腺素和胰岛素信号连接起来.
科学领域:
- 生物化学 生物化学
- 细胞生物学 细胞生物学
- 代谢调节 代谢调节 代谢调节 代谢调节
背景情况:
- 氨基酸3-酶p110α (PI3K p110α) 对于胰岛素信号传递和维持葡萄糖平衡至关重要.
- 识别PI3K p110α活性的新型调节剂对于理解代谢控制至关重要.
研究的目的:
- 为了确定PI3K p110α活动的新型调节者.
- 阐明希波基因酶调节PI3K p110α的机制.
- 研究这种调节对代谢途径的生理后果.
主要方法:
- 人类基因组的查以确定PI3K p110α调节者.
- 酸化部位映射 (T1061) 和功能性检测.
- 希波基因酶 (MST1/2) 的抑制和遗传删除研究.
- 在人类和动物模型中分析胰岛素信号传递,糖解和糖原合成.
主要成果:
- 鉴定出河马激酶 (MST1/2) 是一种新型调节剂,在T1061酸化PI3K p110α,抑制其活性.
- 在T1061的酸化会诱导形状变化,损害PI3K的p110α膜结合.
- 福斯科林或上腺素激活MST1/2抑制了肝细胞和动物组织中的胰岛素信号传递,糖解和糖原合成.
- 对MST1/2的遗传删除或抑制,或对T1061的突变,取消了这些抑制作用.
结论:
- 已经定义了一种由Hippo kinases介导的PI3K信号传递的新型抑制途径.
- 这项研究确立了上腺素信号传递和胰岛素信号传递途径之间的直接联系.
- 这些发现为调节葡萄糖平衡和代谢障碍的潜在治疗点提供了新的见解.
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