A regulated interaction with the UIM protein Eps15 implicates parkin in EGF receptor trafficking and PI(3) K-Akt signalling
A regulated interaction with the UIM protein Eps15 implicates parkin in EGF receptor trafficking and PI(3) K-Akt signalling
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DOI：
10.1038/ncb1441
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发表时间：
2006-08-01
影响因子：
21.3
通讯作者：
Fon, Edward A.
中科院分区：
文献类型：
--
作者：
Fallon, Lara;Belanger, Catherine M. L.;Fon, Edward A.
parkin基因的突变是导致帕金森病常见家族性形式的原因（1，2）。由于parkin编码E3泛素连接酶（3），因此认为蛋白酶体介导的蛋白质降解缺陷在帕金森病的发病机制中具有核心作用（4）。在这里，我们报告了帕金在不依赖蛋白酶体的遍在化途径中的新作用。我们已经确定了parkin和Eps 15之间的调节相互作用，Eps 15是一种参与表皮生长因子（EGF）受体（EGFR）内吞和运输的衔接蛋白（5）。用EGF处理细胞刺激parkin与Eps 15和EGFR结合，并促进parkin介导的Eps 15泛素化。parkin泛素样（Ubl）结构域与Eps 15泛素相互作用基序（UIMs）的结合是parkin介导的Eps 15泛素化所必需的。此外，EGFR内吞作用和降解在parkin缺陷细胞中加速，并且EGFR通过磷酸肌醇3-激酶（PI（3）K）Akt途径的信号传导在parkin敲除小鼠脑中减少。我们认为通过泛素化Eps 15，parkin干扰Eps 15 UIM结合泛素化EGFR的能力（6-8），从而延迟EGFR内化和降解，并促进PI（3）K-Akt信号传导。考虑到Akt在神经元存活中的作用（9），我们的结果对理解帕金森病的发病机制具有广泛的新意义。
Mutations in the parkin gene are responsible for a common familial form of Parkinson's disease(1,2). As parkin encodes an E3 ubiquitin ligase(3), defects in proteasome-mediated protein degradation are believed to have a central role in the pathogenesis of Parkinson's disease(4). Here, we report a novel role for parkin in a proteasome-independent ubiquitination pathway. We have identified a regulated interaction between parkin and Eps15, an adaptor protein that is involved in epidermal growth factor ( EGF) receptor ( EGFR) endocytosis and trafficking(5). Treatment of cells with EGF stimulates parkin binding to both Eps15 and the EGFR and promotes parkin-mediated ubiquitination of Eps15. Binding of the parkin ubiquitin-like ( Ubl) domain to the Eps15 ubiquitin-interacting motifs ( UIMs) is required for parkin-mediated Eps15 ubiquitination. Furthermore, EGFR endocytosis and degradation are accelerated in parkin-deficient cells, and EGFR signalling via the phosphoinositide 3-kinase ( PI( 3) K)Akt pathway is reduced in parkin knockout mouse brain. We propose that by ubiquitinating Eps15, parkin interferes with the ability of the Eps15 UIMs to bind ubiquitinated EGFR(6-8), thereby delaying EGFR internalization and degradation, and promoting PI( 3)K-Akt signalling. Considering the role of Akt in neuronal survival(9), our results have broad new implications for understanding the pathogenesis of Parkinson's disease.