在SHP2上的一个热点化部位驱动着蛋白激活和耐药性
Prashath Karunaraj1,2,3, Remkes Scheele1, Malcolm L Wells4
1Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA.
Nature communications
|March 3, 2026
概括
由SRC家族激酶在氨酸62 (pY62) 中酸化SHP2,激活MAPK信号,导致对SHP2抑制剂的耐药性. 这个pY62位点代表了一种新的癌症药物标.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 在瘤学瘤学.
背景情况:
- SHP2酸酶对于受体氨酸激酶 (RTK) 驱动的RAS/mitogen-activated protein kinase (MAPK) 信号传递至关重要.
- SHP2 抑制剂的临床疗效有限,耐药性机制尚不清楚.
研究的目的:
- 研究SHP2酸化在介导SHP2抑制剂耐药性的作用.
- 确定SHP2激活的新机制和潜在的治疗点.
主要方法:
- 蛋白质组分析以确定SHP2酸化热点.
- 生物化学测试以确定激酶活性和蛋白质相互作用.
- 生物物理分析以描述SHP2的构成和激活.
主要成果:
- 在氨酸62 (pY62) 中的SHP2酸化被确定为RTK驱动瘤中的热点.
- 在Y62.2.上,SRC家族激酶直接化SHP2.
- SHP2Y62D突变模仿构成性激活,导致MAPK通路激活和抵抗SHP2抑制剂.
结论:
- SHP2 pY62酸化是一种对SHP2抑制剂的初级耐药性机制,是复制突变激活的机制.
- 向SHP2 pY62提供了与野生型SHP2抑制独立的独特治疗策略.
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