损失瘤抑制器TMEM127通过破坏膜动力学驱动RET介导的转变
Timothy J Walker1, Eduardo Reyes-Alvarez1, Brandy D Hyndman1
1Division of Cancer Biology and Genetics, Cancer Research Institute, and Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, K7L 3N6, Canada.
bioRxiv : the preprint server for biology
|July 10, 2023
概括
丧失TMEM127会导致受体氨酸激酶 (RTK) 在细胞表面积累,从而导致染细胞瘤 (PCC) 的发展. 这项研究揭示了TMEM127的存在.
科学领域:
- 在瘤学瘤学.
- 细胞生物学 细胞生物学
- 分子生物学分子生物学
背景情况:
- 受体氨酸激酶 (RTK) 调节细胞信号,它们的失调在癌症中很常见.
- 叶红细胞瘤 (PCC) 可能是由RET突变或TMEM127无活化引起的,这是一个参与内体贩运的瘤抑制剂.
- 异常受体贩运在PCC病变发生中的确切作用尚不清楚.
研究的目的:
- 调查TMEM127在调节受体氨酸激酶 (RTK) 贩运中的作用及其对染细胞瘤 (PCC) 的影响.
- 阐明TMEM127损失导致PCC瘤发生的机制.
主要方法:
- 利用细胞培养模型研究TMEM127损失对RET受体氨酸激酶 (RTK) 定位和活性的影响.
- 分析了细胞膜的组织,蛋白质复合体的组合,以及氨酸涂层坑的动力学.
- 评估了细胞表面蛋白质的内化和降解,包括RET.
主要成果:
- 丢失TMEM127导致野生型RET蛋白在细胞表面积累,促进构成性,连接体独立活性.
- 缺少TMEM127会破坏细胞膜组织,损害克拉斯林涂层坑的成熟,并减少RET内部化和降解.
- TMEM127 枯竭导致多个跨膜蛋白质的表面积累,表明蛋白质调节中的更广泛缺陷.
结论:
- TMEM127对于维持膜组织,蛋白质复合体组合和跨膜蛋白质的适当运输至关重要.
- 异常的膜动力学和由此导致的细胞表面积累的生长因子受体,如RET,由TMEM127损失驱动,代表了PCC瘤发生的新机制.
- 这为了解通过改变膜蛋白调节和信号传递来理解染细胞瘤发育提供了新的范式.
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