甲素L介导的EGFR裂变会影响癌症中的细胞内信号通路
Marija Grozdanić1,2, Barbara Sobotič3, Monika Biasizzo1,2
1Department of Biochemistry, Molecular and Structural Biology, Jozef Stefan Institute, Jamova cesta 39, SI-1000 Ljubljana, Slovenia.
Biological chemistry
|October 27, 2023
概括
细胞外甲素L切割表皮生长因子受体 (EGFR),创建一个截断的形式,促进癌细胞的生存和抵抗EGFR抑制剂,如erlotinib和cetuximab.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 生物化学 生化学
背景情况:
- 瘤微环境中的蛋白质分解活性会影响癌症的进展和耐药性.
- 皮表皮生长因子受体 (EGFR) 信号传递对癌症发展至关重要.
- 了解EGFR的修饰是开发有效的癌症疗法的关键.
研究的目的:
- 研究细胞外甲素L在EGFR分裂中的作用.
- 描述截断EGFR变异的功能后果.
- 确定截断EGFR对癌细胞对EGFR抑制剂反应的影响.
主要方法:
- 证明了EGFR的细胞外甲素L介导裂变.
- 在EGFR.上确定特定的裂痕部位.
- 在HeLa细胞中表达一个截断的EGFR突变体.
- 细胞内信号通路和细胞活性的分析.
- 对EGFR氨酸激酶抑制剂 (TKI) erlotinib和单克隆抗体 (mAb) cetuximab的反应的评估.
主要成果:
- 细胞外甲素L在R224处切割EGFR,产生截断的形式.
- 截断的EGFR表现出独立于带结合的构成性激活.
- 表达截断EGFR的细胞显示EGFR和STAT3.3的核局部化和酸化.
- 截断EGFR表达赋予了对erlotinib和cetuximab的耐药性.
结论:
- 细胞外甲素L介导的EGFR裂变产生了一个构成性活跃的,截断的受体.
- 在截断的EGFR表达细胞中,EGFR和STAT3的核转位和酸化有助于抵抗EGFR抑制剂.
- 针对这种裂变或下游信号可能会克服高蛋白质活性癌症的治疗耐药性.
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