Fang S, Ferrone M, Yang C, Jensen J P, Tiwari S, Weissman A M
Regulation of Protein Function Laboratory, Center for Cancer Research, National Cancer Institute, Building 10, Room 1B34, 9000 Rockville Pike, Bethesda, MD 20892-1152, USA.
Proc Natl Acad Sci U S A. 2001 Dec 4;98(25):14422-7. doi: 10.1073/pnas.251401598. Epub 2001 Nov 27.
gp78, also known as the tumor autocrine motility factor receptor, is a transmembrane protein whose expression is correlated with tumor metastasis. We establish that gp78 is a RING finger-dependent ubiquitin protein ligase (E3) of the endoplasmic reticulum (ER). Consistent with this, gp78 specifically recruits MmUBC7, a ubiquitin-conjugating enzyme (E2) implicated in ER-associated degradation (ERAD), through a region distinct from the RING finger. gp78 can target itself for proteasomal degradation in a RING finger- and MmUBC7-dependent manner. Importantly, gp78 can also mediate degradation of CD3-delta, a well-characterized ERAD substrate. In contrast, gp78 lacking an intact RING finger or its multiple membrane-spanning domains stabilizes CD3-delta. gp78 has thus been found to be an example of a mammalian cellular E3 intrinsic to the ER, suggesting a potential link between ubiquitylation, ERAD, and metastasis.
gp78，也被称为肿瘤自分泌运动因子受体，是一种跨膜蛋白，其表达与肿瘤转移相关。我们证实gp78是内质网（ER）的一种依赖于RING指结构的泛素蛋白连接酶（E3）。与此一致的是，gp78通过一个不同于RING指结构的区域特异性招募MmUBC7，一种参与内质网相关降解（ERAD）的泛素结合酶（E2）。gp78能够以依赖于RING指结构和MmUBC7的方式将自身靶向蛋白酶体降解。重要的是，gp78还能介导CD3-δ的降解，CD3-δ是一种特征明确的ERAD底物。相比之下，缺乏完整RING指结构或其多个跨膜结构域的gp78会使CD3-δ稳定。因此，gp78被发现是内质网固有的一种哺乳动物细胞E3的实例，这表明泛素化、ERAD和转移之间可能存在联系。
