Oncogenic activation of the Met receptor tyrosine kinase fusion protein, Tpr-Met, involves exclusion from the endocytic degradative pathway
Oncogenic activation of the Met receptor tyrosine kinase fusion protein, Tpr-Met, involves exclusion from the endocytic degradative pathway
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DOI：
10.1038/sj.onc.1210522
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发表时间：
2007-11-08
期刊：
影响因子：
8
通讯作者：
Park, M.
中科院分区：
文献类型：
--
作者：
Mak, H. H. L.;Peschard, P.;Park, M.
在人类癌症中观察到受体酪氨酸激酶 (RTK) 失调的多种机制。除了功能获得之外，负调控的丧失也会导致 RTK 的致癌激活。许多 RTK 的负调控涉及它们在溶酶体中的内化和降解，这是一个通过泛素化调节的过程。 RTK 癌蛋白在染色体易位后被激活，不再是跨膜蛋白，并且预计将逃脱溶酶体降解。为了测试这一点，我们使用了 Tpr-Met 癌基因，该基因是在肝细胞生长因子受体 (Met) 染色体易位后产生的。与 Met 不同，Tpr-Met 位于细胞质中，并且缺乏 Cbl 泛素连接酶的结合位点。我们确定了 Tpr-Met 的亚细胞定位和/或其 Cbl 结合位点的丢失是否对致癌活性很重要。 Cbl 结合位点的存在和胞质 Tpr-Met 癌蛋白的泛素化不会改变其转化活性。相反，质膜靶向允许Tpr-Met进入内吞途径，并且Tpr-Met转化活性以及蛋白质稳定性以Cbl依赖性方式降低。我们表明，Tpr-Met 的转化部分取决于其逃避正常下调机制的能力。这为染色体易位后激活的许多 RTK 癌蛋白提供了范例。
Multiple mechanisms of dysregulation of receptor tyrosine kinases (RTKs) are observed in human cancers. In addition to gain-of-function, loss of negative regulation also contributes to oncogenic activation of RTKs. Negative regulation of many RTKs involves their internalization and degradation in the lysosome, a process regulated through ubiquitination. RTK oncoproteins activated following chromosomal translocation, are no longer transmembrane proteins, and are predicted to escape lysosomal degradation. To test this, we used the Tpr-Met oncogene, generated following chromosomal translocation of the hepatocyte growth factor receptor (Met). Unlike Met, Tpr-Met is localized in the cytoplasm and also lacks the binding site for Cbl ubiquitin ligases. We determined whether subcellular localization of Tpr-Met, and/or loss of its Cbl-binding site, is important for oncogenic activity. Presence of a Cbl-binding site and ubiquitination of cytosolic Tpr-Met oncoproteins does not alter their transforming activity. In contrast, plasma membrane targeting allows Tpr-Met to enter the endocytic pathway, and Tpr-Met transforming activity as well as protein stability are decreased in a Cbl-dependent manner. We show that transformation by Tpr-Met is in part dependent on its ability to escape normal downregulatory mechanisms. This provides a paradigm for many RTK oncoproteins activated following chromosomal translocation.