Tsai Yien Che, Mendoza Arnulfo, Mariano Jennifer M, Zhou Ming, Kostova Zlatka, Chen Bo, Veenstra Timothy, Hewitt Stephen M, Helman Lee J, Khanna Chand, Weissman Allan M
Laboratory of Protein Dynamics and Signaling, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, USA.
Nat Med. 2007 Dec;13(12):1504-9. doi: 10.1038/nm1686. Epub 2007 Nov 25.
Metastasis is the primary cause of mortality from cancer, but the mechanisms leading to metastasis are poorly understood. In particular, relatively little is known about metastasis in cancers of mesenchymal origins, which are known as sarcomas. Approximately ten proteins have been characterized as 'metastasis suppressors', but how these proteins function and are regulated is, in general, not well understood. Gp78 (also known as AMFR or RNF45) is a RING finger E3 ubiquitin ligase that is integral to the endoplasmic reticulum (ER) and involved in ER-associated degradation (ERAD) of diverse substrates. Here we report that expression of gp78 has a causal role in the metastasis of an aggressive human sarcoma and that this prometastatic activity requires the E3 activity of gp78. Further, gp78 associates with and targets the transmembrane metastasis suppressor, KAI1 (also known as CD82), for degradation. Suppression of gp78 increases KAI1 abundance and reduces the metastatic potential of tumor cells, an effect that is largely blocked by concomitant suppression of KAI1. An inverse relationship between these proteins was confirmed in a human sarcoma tissue microarray. Whereas most previous efforts have focused on genetic mechanisms for the loss of metastasis suppressor genes, our results provide new evidence for post-translational downregulation of a metastasis suppressor by its ubiquitin ligase, resulting in abrogation of its metastasis-suppressing effects.
转移是癌症致死的主要原因，但导致转移的机制却知之甚少。特别是，对于间充质起源的癌症（即肉瘤）中的转移情况了解相对较少。大约有十种蛋白质已被鉴定为“转移抑制因子”，但这些蛋白质的功能以及如何被调控，总体而言还不清楚。Gp78（也称为AMFR或RNF45）是一种环状结构域E3泛素连接酶，它是内质网（ER）的组成部分，并参与多种底物的内质网相关降解（ERAD）。在此我们报告，gp78的表达在一种侵袭性人类肉瘤的转移中起因果作用，并且这种促转移活性需要gp78的E3活性。此外，gp78与跨膜转移抑制因子KAI1（也称为CD82）结合并将其作为降解靶点。抑制gp78会增加KAI1的丰度并降低肿瘤细胞的转移潜能，而同时抑制KAI1则在很大程度上阻断了这种效应。在人类肉瘤组织芯片中证实了这些蛋白质之间的负相关关系。尽管之前的大多数研究都集中在转移抑制基因缺失的遗传机制上，但我们的结果为一种转移抑制因子被其泛素连接酶进行翻译后下调提供了新证据，从而导致其转移抑制作用的丧失。
