Quantity Control of the ErbB3 Receptor Tyrosine Kinase at the Endoplasmic Reticulum
Quantity Control of the ErbB3 Receptor Tyrosine Kinase at the Endoplasmic Reticulum
复制标题
DOI：
10.1128/mcb.05105-11
复制
发表时间：
2011-07-01
影响因子：
5.3
通讯作者：
Carraway, Kermit L., III
中科院分区：
文献类型：
--
作者：
Fry, William H. D.;Simion, Catalina;Carraway, Kermit L., III
ErbB 3受体酪氨酸激酶参与多种发育过程，其过表达和异常激活促进肿瘤进展和治疗抗性。越来越多的证据表明，肿瘤过度表达可能是由转录后负调控机制的丧失介导的，如蛋白质降解，通常保持受体水平在检查中。我们以前的研究表明，环指E3泛素连接酶Nrdp 1，一种在乳腺癌和其他肿瘤类型中丢失的蛋白质，通过介导配体非依赖性受体泛素化和降解来抑制ErbB 3水平。在这里，我们表明，Nrdp 1优先与新生形式的ErbB 3，以加速其降解，我们表明，这两种蛋白质共定位在内质网（ER）。阻断ErbB 3从内质网的退出并不影响Nrdp 1介导受体泛素化或降解的能力，而保守的内质网相关降解（ERAD）途径ATP酶VCP/p97的功能性破坏导致Nrdp 1依赖性的泛素化ErbB 3积累，但阻断受体降解。进一步的证据表明，Nrdp 1靶向降解的ErbB 3是正确折叠和完全功能性的。总的来说，这些观察结果指出了一种新的受体酪氨酸激酶数量控制机制，其中稳态水平的信号传导受体是由ER定位的降解途径。
The ErbB3 receptor tyrosine kinase contributes to a variety of developmental processes, and its overexpression and aberrant activation promote tumor progression and therapeutic resistance. Accumulating evidence suggests that tumor overexpression may be mediated by the loss of posttranscriptional negative regulatory mechanisms, such as protein degradation, that normally keep receptor levels in check. Our previous studies indicate that the RING finger E3 ubiquitin ligase Nrdp1, a protein lost in breast and other tumor types, suppresses ErbB3 levels by mediating ligand-independent receptor ubiquitination and degradation. Here we demonstrate that Nrdp1 preferentially associates with the nascent form of ErbB3 to accelerate its degradation, and we show that the two proteins colocalize at the endoplasmic reticulum (ER). Blocking the exit of ErbB3 from the ER does not affect the ability of Nrdp1 to mediate receptor ubiquitination or degradation, while functional disruption of the conserved ER-associated degradation (ERAD) pathway ATPase VCP/p97 leads to the Nrdp1-dependent accumulation of ubiquitinated ErbB3 but blocks receptor degradation. Further evidence indicates that the ErbB3 targeted by Nrdp1 for degradation is properly folded and fully functional. Collectively, these observations point to a novel mechanism of receptor tyrosine kinase quantity control wherein steady-state levels of signaling-competent receptor are dictated by an ER-localized degradation pathway.