通过激活线粒体复合体,SHP2E76K的相分离促进了介质干细胞的恶性转变

通过激活线粒体复合体,SHP2E76K的相分离促进了介质干细胞的恶性转变

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Updated: Jul 1, 2025

Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors

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Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors

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Chen Kan¹, Zhenya Tan¹, Liwei Liu²

¹Department of Pathophysiology, School of Basic Medical Sciences, Stem Cell Regeneration Research Center, Anhui Medical University, Hefei, China.

JCI insight

|March 7, 2024

概括

激活SHP2 (Src同源区2含蛋白氨酸酸酶2) 的突变,通过引起线粒体过活化,驱动肉瘤干细胞样细胞的形成. 抑制SHP2液-液相分离 (LLPS) 是一种潜在的癌症治疗点.

科学领域:

细胞生物学细胞生物学
分子瘤学分子瘤学
生物化学生物化学

背景情况:

介酶干细胞 (MSCs) 可以经历恶性转变和异常分化.
蛋白质氨酸酸酶SHP2调节细胞分化,增殖和转化,但其在MSC命运中的作用尚不清楚.
在SHP2中激活突变与各种癌症有关.

研究的目的:

调查激活SHP2E76K突变在MSC命运决定中的作用.
阐明SHP2E76K突变驱动恶性转变的机制.
探索SHP2LLPS作为一个潜在的治疗目标.

主要方法:

对具有SHP2E76K突变的小鼠MSC进行分析.
评估线粒体代谢和复合物I和III活动.
使用突变和抑制剂对SHP2液态液态相分离 (LLPS) 的研究.

主要成果:

具有SHP2E76K突变的MSCs转化为类似肉瘤干细胞.
SHP2E76K突变通过激活复合物I和III引起了过度活跃的线粒体代谢.
在SHP2E76KMSC中观察到SHP2LLPS,导致复杂I和III过活化和恶性转变.

结论:

SHP2 LLPS驱动线粒体过活化,促进SHP2E76KMSCs的恶性转变.
抑制线粒体复合物I和III或SHP2LLPS可以防止恶性转变.
准SHP2LLPS为SHP2相关癌症提供了潜在的治疗策略.

关键词:

成人的干细胞是成人的干细胞.癌症癌症癌症癌症小鼠的干细胞是什么?在瘤学瘤学.干细胞是一种干细胞.

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