Cool-1 functions as an essential regulatory node for EGF receptor-and Src-mediated cell growth
Cool-1 functions as an essential regulatory node for EGF receptor-and Src-mediated cell growth
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DOI：
10.1038/ncb1453
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发表时间：
2006-09-01
影响因子：
21.3
通讯作者：
Cerione, Richard A.
中科院分区：
文献类型：
--
作者：
Feng, Qiyu;Baird, Dan;Cerione, Richard A.
Cool-1（从文库 1 中克隆出来）在调节表皮生长因子受体 (EGFR) 降解方面发挥着关键作用。在这里，我们表明 Cool-1 通过充当 Cdc42 的上游激活剂和下游靶标来执行此功能。 Cool-1 的 EGF 依赖性磷酸化使其能够充当 Cdc42 的核苷酸交换因子，并与 E3 连接酶 Cbl 形成复合物，从而调节 Cbl 催化的 EGFR 降解。 EGF 依赖性磷酸化通常是短暂的；然而，Cool-1 磷酸化在表达 v-Src 的细胞中持续存在，对于细胞转化以及 v-Src 诱导的小鼠肿瘤形成至关重要。这些发现表明，受调节的 Cool-1 磷酸化对于维持 EGFR 和 Src 的正常信号传导与异常生长和转化之间的平衡是必要的。
Cool-1 (cloned-out of library 1) has a key role in regulating epidermal growth factor receptor (EGFR) degradation. Here, we show that Cool-1 performs this function by functioning as both an upstream activator and downstream target for Cdc42. EGF-dependent phosphorylation of Cool-1 enables it to act as a nucleotide exchange factor for Cdc42 and to form a complex with the E3 ligase Cbl, thus regulating Cbl-catalysed EGFR degradation. The EGF-dependent phosphorylation is normally transient; however, Cool-1 phosphorylation is sustained in cells expressing v-Src and is essential for cellular transformation, as well as for v-Src-induced tumour formation in mice. These findings demonstrate that the regulated phosphorylation of Cool-1 is necessary to maintain the balance between normal signalling by EGFR and Src versus aberrant growth and transformation.