Nectin-like molecule-5/Tage4 enhances cell migration in an integrin-dependent, Nectin-3-independent manner
Nectin-like molecule-5/Tage4 enhances cell migration in an integrin-dependent, Nectin-3-independent manner
复制标题
DOI：
10.1074/jbc.m312969200
复制
发表时间：
2004-04-23
影响因子：
4.8
通讯作者：
Takai, Y
中科院分区：
文献类型：
--
作者：
Ikeda, W;Kakunaga, S;Takai, Y
细胞迁移在转化细胞的侵袭和胚胎间充质细胞向周围组织的分散中起作用。我们发现，在由致癌Ras转化的NIH3T3细胞（V12Ras-NIH3T3细胞）中，igg样的Necl-5/Tage4上调，并与Ca2+独立的igg样细胞粘附分子nectin-3异亲性反式相互作用，最终增强其细胞间运动。我们在这里表明Necl-5以不依赖于nectin-3的方式进一步增强细胞迁移。利用表达Necl-5、NIH3T3细胞和V12Ras-NIH3T3细胞的各种突变体的L成纤维细胞进行的研究表明，Necl-5增强了血清和血小板来源的生长因子诱导的细胞迁移。Necl-5的胞外区域是细胞定向迁移所必需的，但不是随机细胞运动所必需的。Necl-5的细胞质区对于细胞的定向和随机运动都是必需的。Necl-5与整合素α (V) β(3)在迁移细胞的前缘共定位。使用整合素α (V) β(3)的抑制剂或激活剂或Necl-5的显性负突变体进行的分析表明，Necl-5与整合素α (V) β(3)在细胞运动中的功能关联。Cdc42和Rac小G蛋白被Necl-5激活，是血清诱导的、Necl-5增强的细胞运动所必需的。这些结果表明，当细胞不与其他细胞接触时，Necl-5以整合素依赖、连接蛋白3独立的方式调节血清和血小板来源的生长因子诱导的细胞迁移。我们进一步表明，V12Ras-NIH3T3细胞的运动性增强和转移至少部分是Necl-5上调的结果。
Cell migration plays roles in invasion of transformed cells and scattering of embryonic mesenchymal cells into surrounding tissues. We have found that Ig-like Necl-5/Tage4 is up-regulated in NIH3T3 cells transformed by an oncogenic Ras (V12Ras-NIH3T3 cells) and heterophilically trans-interacts with a Ca2+-independent Ig-like cell adhesion molecule nectin-3, eventually enhancing their intercellular motility. We show here that Necl-5 furthermore enhances cell migration in a nectin-3-independent manner. Studies using L fibroblasts expressing various mutants of Necl-5, NIH3T3 cells, and V12Ras-NIH3T3 cells have revealed that Necl-5 enhances serum- and platelet-derived growth factor-induced cell migration. The extracellular region of Necl-5 is necessary for directional cell migration, but not for random cell motility. The cytoplasmic region of Necl-5 is necessary for both directional and random cell movement. Necl-5 colocalizes with integrin alpha(V)beta(3) at leading edges of migrating cells. Analyses using an inhibitor or an activator of integrin alpha(V)beta(3) or a dominant negative mutant of Necl-5 have shown the functional association of Necl-5 with integrin alpha(V)beta(3) in cell motility. Cdc42 and Rac small G proteins are activated by the action of Necl-5 and required for the serum-induced, Necl-5-enhanced cell motility. These results indicate that Necl-5 regulates serum- and platelet-derived growth factor-induced cell migration in an integrin-dependent, nectin3- independent manner, when cells do not contact other cells. We furthermore show here that enhanced motility and metastasis of V12Ras-NIH3T3 cells are at least partly the result of up-regulated Necl-5.