MGAT3-mediated glycosylation of tetraspanin CD82 at asparagine 157 suppresses ovarian cancer metastasis by inhibiting the integrin signaling pathway
MGAT3-mediated glycosylation of tetraspanin CD82 at asparagine 157 suppresses ovarian cancer metastasis by inhibiting the integrin signaling pathway
复制标题
MGAT3介导的四跨膜蛋白CD82在天冬酰胺157处的糖基化通过抑制整合素信号通路抑制卵巢癌转移
DOI：
10.7150/thno.43865
复制
发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Yue, Shijing
中科院分区：
文献类型：
--
作者：
Li, Jun;Xu, Jiawen;Yue, Shijing
背景资料：四跨膜蛋白是跨膜蛋白家族中的一员，主要通过将质膜组织成微结构域来发挥作用。CD82是四跨膜蛋白家族的一员，在许多恶性肿瘤中是一种有效的肿瘤转移抑制剂。CD82是一种高度糖基化的蛋白质，然而，这种翻译后修饰是否以及如何影响CD82功能和癌症转移仍然是未知的。方法：检测人卵巢癌原发灶和转移灶配对组织中CD82糖基化的表达。在体外和体内对CD82的各种糖基化位点进行功能研究。结果如下：我们证明，CD82糖基化在Asn157是必要的CD82介导的抑制卵巢癌细胞的迁移和转移在体外和体内。从机制上讲，我们发现CD82糖基化是破坏整合素α5β1介导的细胞与丰富的细胞外基质蛋白纤连蛋白粘附的关键。因此，糖基化的CD82抑制负责诱导细胞迁移所需的细胞骨架重排的整联蛋白信号传导途径。此外，我们发现糖基转移酶MGAT 3负责卵巢癌细胞中的CD82糖基化。转移性卵巢癌表达降低水平的MGAT 3，这反过来可能导致受损的CD82糖基化。结论：我们的工作暗示了通过MGAT3介导的四跨膜蛋白CD82在天冬酰胺157处的糖基化来调节卵巢癌转移的途径。
Background: Tetraspanins constitute a family of transmembrane spanning proteins that function mainly by organizing the plasma membrane into micro-domains. CD82, a member of tetraspanins, is a potent inhibitor of cancer metastasis in numerous malignancies. CD82 is a highly glycosylated protein, however, it is still unknown whether and how this post-translational modification affects CD82 function and cancer metastasis. Methods: The glycosylation of CD82 profiles are checked in the paired human ovarian primary and metastatic cancer tissues. The functional studies on the various glycosylation sites of CD82 are performed in vitro and in vivo. Results: We demonstrate that CD82 glycosylation at Asn157 is necessary for CD82-mediated inhibition of ovarian cancer cells migration and metastasis in vitro and in vivo. Mechanistically, we discover that CD82 glycosylation is pivotal to disrupt integrin α5β1-mediated cellular adhesion to the abundant extracellular matrix protein fibronectin. Thereby the glycosylated CD82 inhibits the integrin signaling pathway responsible for the induction of the cytoskeleton rearrangements required for cellular migration. Furthermore, we reveal that the glycosyltransferase MGAT3 is responsible for CD82 glycosylation in ovarian cancer cells. Metastatic ovarian cancers express reduced levels of MGAT3 which in turn may result in impaired CD82 glycosylation. Conclusions: Our work implicates a pathway for ovarian cancers metastasis regulation via MGAT3 mediated glycosylation of tetraspanin CD82 at asparagine 157.