通过GRB2与焦点粘附激酶结合,与Ras通路连接的整合素介导信号传导
D D Schlaepfer1, S K Hanks, T Hunter
1Molecular Biology and Virology Laboratory, Salk Institute, San Diego, California 92186.
Nature
|December 22, 1994
概括
纤维素结合因特林激活了焦粘附激酶 (FAK) 信号传递. 这促进了细胞粘附,并通过GRB2和c-Src相互作用激活了Ras/MAPK通路.
科学领域:
- 细胞生物学 细胞生物学
- 分子生物学分子生物学
- 生物化学 生物化学
背景情况:
- 焦粘附激酶 (FAK) 是一种细胞质蛋白-氨酸激酶 (PTK),它与细胞粘附部位的整合素受体局部化.
- 整体素与细胞外矩阵蛋白质 (如纤维蛋白) 的结合触发了FAK氨酸酸化.
研究的目的:
- 研究FAK,GRB2和c-Src在整合素介导信号通路中的作用.
- 阐明将整合素参与与基因激活蛋白激酶 (MAPK) 激活联系起来的机制.
主要方法:
- 研究了NIH3T3纤维细胞粘附于纤维菌素.
- 利用共免疫沉来评估体内蛋白质与蛋白质的相互作用.
- 用突变的FAK蛋白进行了体外结合试验.
主要成果:
- 纤维素诱导的细胞粘附促进了GRB2和c-Src与FAK的关联.
- 这种关联是由GRB2的SH2域与氨酸化FAK结合的介导.
- 在FAK tyrosine 925的突变阻断了GRB2的结合,表明其关键作用.
- 观察到MAPK的激活是对纤维内素刺激的反应.
结论:
- 整体素与纤维素结合会启动一个涉及FAK,c-Src和GRB2.2的信号复合体.
- 在 Tyr 925 中的 FAK 化产生了 GRB2 的结合位点,将整合素信号与 Ras/MAPK 途径联系起来.
相关概念视频
The Ras Gene
The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
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Amplifying Signals via Enzymatic Cascade
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Three regulatory proteins control their activity:
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MAPK Signaling Cascades
Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
Intracellular Signaling Affects Focal Adhesions
Integrins act both as extracellular input receivers and as intracellular processing activators. As their name suggests, integrins are entirely integrated into the membrane structure. Their hydrophobic membrane-spanning regions interact with the phospholipid bilayer's hydrophobic region. These membrane receptors provide extracellular attachment sites for effectors like hormones and growth factors. They activate intracellular response cascades when their effectors are bound and active.
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