Chaperone-dependent E3 ubiquitin ligase CHIP mediates a degradative pathway for c-ErbB2 Neu
Chaperone-dependent E3 ubiquitin ligase CHIP mediates a degradative pathway for c-ErbB2 Neu
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DOI：
10.1073/pnas.202365899
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发表时间：
2002-10-01
影响因子：
11.1
通讯作者：
Neckers, L
中科院分区：
文献类型：
--
作者：
Xu, WP;Marcu, M;Neckers, L
跨膜受体酪氨酸激酶ErbB2的过度表达在多种恶性肿瘤中很常见，包括乳腺癌和卵巢癌。ERBB2抵抗c-Cbl介导的降解，c-Cbl是一种E3泛素连接酶，负责配体诱导ErbB1(表皮生长因子受体)的泛素化。由于ErbB2对降解的抗性，它是ErbB家族其他成员首选的二聚化伙伴，其在体内的过度表达与预后不良有关。我们现在证明，伴侣结合泛素连接酶芯片有效地泛素化和下调ErbB2。ChIP的表达缩短了新生和成熟ErbB2蛋白的半衰期。体外泛素化实验表明，CHIP是ErbB2的泛素连接酶，外源表达和内源性CHIP均与该激酶共沉淀。此外，芯片与ErbB2的结合需要伴侣中间体，并被伴侣结合药物格尔达那霉素增加，格尔达那霉素是ErbB2泛素化和降解的有效刺激因子。这些数据描述了一条以前未知的通路，可以通过药物操作来调节ErbB2的稳定性。
Overexpression of the transmembrane receptor tyrosine kinase ErbB2 is common in multiple malignancies, including breast and ovarian cancer. ErbB2 is resistant to degradation mediated by c-Cbl, the E3 ubiquitin ligase responsible for ligand-induced ubiquitination of ErbB1 (epidermal growth factor receptor). Because of its resistance to degradation, ErbB2 is the preferred dimerization partner for other members of the ErbB family, and its overexpression in vivo is associated with poor prognosis. We now show that the chaperone-binding ubiquitin ligase CHIP efficiently ubiquitinates and down-regulates ErbB2. CHIP expression shortens the half-life of both nascent and mature ErbB2 protein. In vitro ubiquitination assay shows that CHIP serves as a ubiquitin ligase for ErbB2, and both exogenously expressed and endogenous CHIP coprecipitate with the kinase. Furthermore, CHIP association with ErbB2 requires a chaperone intermediate and is increased by the chaperone-binding drug geldanamycin, a potent stimulator of ErbB2 ubiquitination and degradation. These data describe a previously unrecognized pathway, amenable to pharmacologic manipulation, that mediates ErbB2 stability.