hSpry2 Is Targeted to the Ubiquitin-Dependent Proteasome Pathway by c-Cbl

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• 作者：Amy B. Hall ; Natalia Jura ; John DaSilva ; Yeon Joo Jang ; Delquin Gong ; Dafna Bar-Sagi
• 关键词：CELLBIO ; DNA ; RNA
• 刊名：Current Biology
• 出版年：2003
• 出版时间：18 February 2003
• 年：2003
• 卷：13
• 期：4
• 页码：308-314
• 全文大小：410 K

文摘

Sprouty was originally identified in a genetic screen in Drosophila as an antagonist of fibroblast (FGF) and epidermal growth factor (EGF) signaling [1 and 2]. Subsequently, four vertebrate homologs were discovered; among these, the human homolog Sprouty 2 (hSpry2) contains the highest degree of sequence homology to the Drosophila protein [3 and 4]. It has been shown that hSpry2 interacts directly with c-Cbl, an E3-ubiquitin ligase, which promotes the downregulation of receptor tyrosine kinases (RTKs) [5]. In this study, we have investigated the functional consequences of the association between hSpry2 and c-Cbl. We have found that hSpry2 is ubiquitinated by c-Cbl in an EGF-dependent manner. EGF stimulation induces the tyrosine phosphorylation of hSpry2, which in turn enhances the interaction of hSpry2 with c-Cbl. The c-Cbl-mediated ubiquitination of hSpry2 targets the protein for degradation by the 26S proteasome. An enhanced proteolytic degradation of hSpry2 is also observed in response to FGF stimulation. The FGF-induced degradation of hSpry2 limits the duration of the inhibitory effect of hSpry2 on extracellular signal-regulated kinase (ERK) activation and enables the cells to recover their sensitivity to FGF stimulation. Our results indicate that the interaction of hSpry2 with c-Cbl might serve as a mechanism for the downregulation of hSpry2 during receptor tyrosine kinase signaling.