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通过扩大其与GAP蛋白的结合接口,K128无处不在限制了RAS活性

Wout Magits¹, Mikhail Steklov¹, Hyunbum Jang²

¹VIB-KU Leuven Center for Cancer Biology, VIB, 3000, Leuven, Belgium.

The EMBO journal

|June 10, 2024

概括

氨酸128对RAS蛋白的泛化增强了它们与GTPase激活蛋白 (GAPs) 的相互作用,抑制了癌细胞的生长. 减少无处不在促进RAS信号传递和胰腺瘤的发展.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
细胞信号传递细胞信号传递

背景情况:

在各种癌症中,RAS信号通路经常失调.
控制人类病理中的RAS活动的机制需要进一步阐明.
氨酸128 (K128) NRAS和KRAS的无处不在是癌症中普遍发生的修饰性降低.

研究的目的:

调查K128无化在RAS信号传递和癌症中的功能作用.
确定K128的无处不在如何影响RAS与GTPase激活蛋白 (GAPs) 的相互作用.
探索改变K128无处不在的后果在野生类型和突变RAS驱动的癌症中.

主要方法:

在癌症细胞系和组织中研究K128的无处不在.
利用细胞培养刺激与生长因子和细胞因子.
分析了RAS-GAP相互作用和下游信号通路 (RAL/TBK1).
评估了对瘤生长和衰老相关的分泌表型的影响.

主要成果:

K128无处不在增强了与GAPs (NF1,RASA1) 的结合,促进了GTP的水解,并限制了野生类型的RAS激活.
暂时的K128无处可见性限制了在生长因子刺激时RAS激活.
在KRAS突变细胞中,K128无处不在抑制瘤生长,通过抑制RAL/TBK1信号传递和自身隐性回路.
降低的K128无处不在激活野生型和突变RAS,诱导与衰老相关的分泌表型并促进胰腺瘤发生.

结论:

K128的无处不在作用是RAS信号的关键负调节器.
这种修改会影响正常和癌症条件下的RAS活性.
准K128无处不在可能为RAS驱动的癌症提供治疗策略,特别是胰腺癌.

关键词:

NF1 NF1 是一个字母.在 RAS 互动组中.在 RAS 信号传输中.与衰老相关的分泌体表现型在Ubiquitination中使用.

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