Interaction of nectin-like molecule 2 with integrin α 6β 4and inhibition of disassembly of integrin α 6β 4from hemidesmosomes

Abstract

In normal epithelial cells, integrin α 6β 4 is abundantly expressed and forms hemidesmosomes, which is a cellular structure that mediates cell-extracellular matrix binding. In many types of cancer cells, integrin α 6β 4 is up-regulated, laminin is cleaved, and hemidesmosomes are disrupted, eventually causing an enhancement of cancer cell movement and facilitation of their invasion. We previously showed that the immunoglobulin-like cell adhesion molecule Necl-2 (Nectin-like molecule 2), known as a tumor suppressor, inhibits cancer cell movement by suppressing the ErbB3/ErbB2 signaling. We show here that Necl-2 interacts in cis with integrin α 6β 4. The binding of Necl-2 with integrin β 4 was mediated by its extracellular region. In human colorectal adenocarcinoma Caco-2 cells, integrin α 6β 4was localized at hemidesmosomes. Small interfering RNA-mediated suppression of Necl-2 expression enhanced the phorbol ester-induced disruption of the integrin α 6β 4 complex at hemidesmosomes, whereas expression of Necl-2 suppressed the disruption of this structure. These results indicate that tumor-suppressive functions of Necl-2 are mediated by the stabilization of the hemidesmosome structure in addition to the inhibition of the ErbB3/ErbB2 signaling. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.