c-Kit-mediated overlapping and unique functional and biochemical outcomes via diverse signaling pathways
c-Kit-mediated overlapping and unique functional and biochemical outcomes via diverse signaling pathways
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DOI：
10.1128/mcb.24.3.1401-1410.2004
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发表时间：
2004-02-01
影响因子：
5.3
通讯作者：
Kapur, R
中科院分区：
文献类型：
--
作者：
Hong, L;Munugalavadla, V;Kapur, R
理解受体酪氨酸激酶信号传导的一个关键问题是不同信号传导途径在调节细胞生长、存活和迁移中的个体贡献。我们产生了一个功能和生物化学惰性的c-Kit受体，缺乏7个早期信号通路的结合位点。恢复突变的c-Kit受体中的Src家族激酶（SFK）结合位点恢复了细胞存活和迁移，但仅部分挽救了增殖，并且与Ras/促分裂原活化蛋白激酶、Rac/JNK激酶和磷脂酰肌醇3-激酶（PI-3激酶）/Akt途径的挽救有关。相比之下，恢复突变受体中的PI-3激酶结合位点不影响细胞增殖，但导致细胞存活和迁移的适度校正，尽管PI-3激酶/Akt途径的激活得到了完全拯救。令人惊讶的是，恢复Grb 2、Grb 7或磷脂酶C-T的结合位点对细胞生长或存活、迁移或任何下游信号通路的激活没有影响。这些结果表明，SFKs在控制多种细胞功能和通过c-Kit激活不同的生化途径中发挥独特的作用。
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-T 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.