不同的EGF诱导的受体二极体构造用于信号和内部化
Jordi Haubrich1, Jurriaan M Zwier2, Fabienne Charrier-Savournin2
1Institut de Génomique Fonctionnelle, University of Montpellier, CNRS, INSERM, Montpellier Cedex 5, France.
概括
皮表皮肤生长因子受体 (EGFR) 分解是由EGF和氨酸激酶抑制剂诱导的. 细胞内二元构造,而不是信号,决定了EGFR内部化,提供了新的癌症治疗策略.
科学领域:
- 生物化学 生化学
- 分子生物学分子生物学
- 细胞生物学 细胞生物学
背景情况:
- 皮表皮生长因子受体 (EGFR) 激活和内化机制对于癌症治疗至关重要,但仍有争议.
- 了解agonists是否形成EGFR二元体或对先前存在的二元体起作用是关键.
研究的目的:
- 提供EGF诱导的EGFR二分体形成的直接证据.
- 研究氨酸激酶 (TK) 抑制剂对EGFR二分化和内部化的作用.
- 确定细胞内TK二分体构成在EGFR内化中的作用.
主要方法:
- 在快速标记的EGFR子单元之间利用Förster共振能量转移 (FRET) 来量化二次体的形成.
- 评估了EGF和各种TK抑制剂 (Erlotinib,Lapatinib) 对EGFR二分化的影响.
- 在TK抑制剂的存在下监测EGF诱导的EGFR内化.
主要成果:
- 根据FRET的证实,EGF激动剂显著增加了EGFR二元体的形成.
- 埃洛尼布类TK抑制剂诱导EGFR二元体的形成,即使结合域不活跃.
- 克抑制剂阻断EGFR信号传递,但不抑制EGF诱导的内部化;只有埃洛提尼布促进不对称的二元体减缓了内部化.
结论:
- EGFR内部化主要由细胞内TK二元体的形状调节,而不是EGFR信号传递.
- 针对EGFR的TK抑制剂存在不同的作用模式.
- 这些发现为控制癌症治疗中的EGFR信号提供开辟了新的途径.
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