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Nectin-like Molecule-5/Tage4 Enhances Cell Migration in an Integrin-dependent, Nectin-3-independent Manner

2004; Elsevier BV; Volume: 279; Issue: 17 Linguagem: Inglês

10.1074/jbc.m312969200

1083-351X

Wataru Ikeda, Shigeki Kakunaga, Kyoji Takekuni, Tatsushi Shingai, Keiko Satoh, Koji Morimoto, Masakazu Takeuchi, Toshio Imai, Yoshimi Takai,

Proteoglycans and glycosaminoglycans research

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 Ca 2+ -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 α V β 3 at leading edges of migrating cells. Analyses using an inhibitor or an activator of integrin α V β 3 or a dominant negative mutant of Necl-5 have shown the functional association of Necl-5 with integrin α V β 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, nectin-3-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.