Hong Li, Munugalavadla Veerendra, Kapur Reuben
Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Mol Cell Biol. 2004 Feb;24(3):1401-10. doi: 10.1128/MCB.24.3.1401-1410.2004.
A critical issue in understanding receptor tyrosine kinase signaling is the individual contribution of diverse signaling pathways in regulating cellular growth, survival, and migration. We generated a functionally and biochemically inert c-Kit receptor that lacked the binding sites for seven early signaling pathways. Restoring the Src family kinase (SFK) binding sites in the mutated c-Kit receptor restored cellular survival and migration but only partially rescued proliferation and was associated with the rescue of the Ras/mitogen-activated protein kinase, Rac/JNK kinase, and phosphatidylinositol 3-kinase (PI-3 kinase)/Akt pathways. In contrast, restoring the PI-3 kinase binding site in the mutated receptor did not affect cellular proliferation but resulted in a modest correction in cell survival and migration, despite a complete rescue in the activation of the PI-3 kinase/Akt pathway. Surprisingly, restoring the binding sites for Grb2, Grb7, or phospholipase C-gamma had no effect on cellular growth or survival, migration, or activation of any of the downstream signaling pathways. These results argue that SFKs play a unique role in the control of multiple cellular functions and in the activation of distinct biochemical pathways via c-Kit.
理解受体酪氨酸激酶信号传导中的一个关键问题是多种信号通路在调节细胞生长、存活和迁移中的各自作用。我们构建了一种功能和生化上无活性的c-Kit受体，该受体缺乏七个早期信号通路的结合位点。在突变的c-Kit受体中恢复Src家族激酶（SFK）结合位点可恢复细胞存活和迁移，但仅部分挽救增殖，且与Ras/丝裂原活化蛋白激酶、Rac/JNK激酶和磷脂酰肌醇3激酶（PI-3激酶）/Akt信号通路的挽救相关。相比之下，在突变受体中恢复PI-3激酶结合位点并不影响细胞增殖，但尽管PI-3激酶/Akt信号通路完全被挽救，细胞存活和迁移仅得到适度纠正。令人惊讶的是，恢复Grb2、Grb7或磷脂酶C-γ的结合位点对细胞生长、存活、迁移或任何下游信号通路的激活均无影响。这些结果表明，SFK在通过c-Kit控制多种细胞功能和激活不同生化信号通路中发挥独特作用。
