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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >The serine/threonine kinase cyclin G-associated kinase regulates epidermal growth factor receptor signaling.
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The serine/threonine kinase cyclin G-associated kinase regulates epidermal growth factor receptor signaling.

机译：丝氨酸/苏氨酸激酶细胞周期蛋白G相关激酶调节表皮生长因子受体信号传导。

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摘要

Cyclin G-associated kinase (GAK) is a serine/threonine kinase that features high homology outside its kinase domain with auxilin. Like auxilin, GAK has been shown to be a cofactor for uncoating clathrin vesicles in vitro. We investigated epidermal growth factor (EGF) receptor-mediated signaling in cells, in which GAK is down-regulated by small hairpin RNAs. Here, we report that down-regulation of GAK by small hairpin RNA has two pronounced effects on EGF receptor signaling: (i) the levels of receptor expression and tyrosine kinase activity go up by >50-fold; and (ii) the spectrum of downstream signaling is significantly changed. One very obvious result is a large increase in the levels of activated extracellular signal-regulated kinase 5 and Akt. These two effects of GAK down-regulation result from, at least in part, alterations in receptor trafficking, the most striking of which is the persistence of EGF receptor in altered cellular compartment along with activated extracellular signal-regulated kinase 5. The alterations resulting from GAK down-regulation can have distinctive biological consequences: In CV1P cells, down-regulation of GAK results in outgrowth of cells in soft agar, raising the possibility that loss of GAK function may promote tumorigenesis.
机译：细胞周期蛋白G相关激酶（GAK）是一种丝氨酸/苏氨酸激酶，在其与生长素的激酶结构域外具有高度同源性。与生长素一样，GAK已被证明是体外释放网格蛋白囊泡的辅因子。我们研究了细胞中的表皮生长因子（EGF）受体介导的信号传导，其中GAK被小发夹RNA下调。在这里，我们报道小发夹RNA下调GAK对EGF受体信号传导有两个明显的影响：（i）受体表达水平和酪氨酸激酶活性增加> 50倍； （ii）下游信令的频谱发生了显着变化。一个非常明显的结果是活化的细胞外信号调节激酶5和Akt的水平大量增加。 GAK下调的这两种作用至少部分是由于受体运输的改变引起的，其中最引人注目的是EGF受体与活化的细胞外信号调节激酶5一起在改变的细胞室中的持久性。 GAK的下调可能具有独特的生物学后果：在CV1P细胞中，GAK的下调导致软琼脂中细胞的生长，从而增加了GAK功能丧失可能促进肿瘤发生的可能性。

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