HSpry2 is targeted to the ubiquitin-dependent proteasome pathway by c-CbI
HSpry2 is targeted to the ubiquitin-dependent proteasome pathway by c-CbI
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DOI：
10.1016/s0960-9822(03)00086-1
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发表时间：
2003-02-18
期刊：
影响因子：
9.2
通讯作者：
Bar-Sagi, D
中科院分区：
文献类型：
--
作者：
Hall, AB;Jura, N;Bar-Sagi, D
最初在果蝇的基因筛选中发现，Sprouty是成纤维细胞（FGF）和表皮生长因子（EGF）信号的拮抗剂[1,2]。随后，发现了四种脊椎动物的同源物；其中，人类同源物Sprouty 2 （hSpry2）与果蝇蛋白的序列同源程度最高[3,4]。研究表明，hSpry2直接与e3泛素连接酶c-Cbl相互作用，促进受体酪氨酸激酶（RTKs）[5]的下调。在这项研究中，我们研究了hSpry2和c-Cbl之间关联的功能后果。我们发现hSpry2以依赖egf的方式被c-Cbl泛素化。EGF刺激诱导hSpry2的酪氨酸磷酸化，进而增强hSpry2与c-Cbl的相互作用。c- cl介导的hSpry2泛素化以26S蛋白酶体降解该蛋白为目标。在FGF刺激下，hSpry2蛋白水解降解增强。FGF诱导的hSpry2降解限制了hSpry2对细胞外信号调节激酶（ERK）激活抑制作用的持续时间，并使细胞恢复对FGF刺激的敏感性。我们的研究结果表明，hSpry2与c-Cbl的相互作用可能是受体酪氨酸激酶信号传导过程中hSpry2下调的机制。
Sprouty was originally identified in a genetic screen in Drosophila as an antagonist of fibroblast (FGF) and epidermal growth factor (EGF) signaling [1, 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, 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.