Abstract
In normal epithelial cells, integrin α(6)β(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(6)β(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(6)β(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(6)β(4) was localized at hemidesmosomes. Small interfering RNA-mediated suppression of Necl-2 expression enhanced the phorbol ester-induced disruption of the integrin α(6)β(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.
Highlights
Necl-2 is an Ig-like cell-cell adhesion molecule, which belongs to the Necl family [1]
Necl-2 was originally deposited to GenBankTM in 1998; IgSF4a was identified as a candidate for a tumor suppressor gene in the loss of heterozygosity region of chromosome at 11q23.2 [4]; RA175 was identified as a gene highly expressed during neuronal differentiation of embryonic carcinoma cells [7]; SgIGSF was identified as a gene expressed in spermatogenic cells during earlier stages of spermatogenesis [6]; TSLC1 was identified as a tumor suppressor in human non-small cell lung cancer [5]; and SynCAM1 was identified as a brain-specific synaptic adhesion molecule [8]
FLAG-tagged Necl-2 (FLAG-Necl-2) or FLAG alone together with integrin ␣64, ␣51, or ␣61 were co-expressed in HEK293 cells, and the cells were cultured in suspension
Summary
Necl-2 (nectin-like molecule 2) is an Ig-like cell-cell adhesion molecule, which belongs to the Necl family [1]. Integrin ␣64 is abundantly expressed and forms hemidesmosomes, which is a cellular structure that mediates cell-extracellular matrix binding. These results indicate that the integrin ␣64-dependent structure most likely corresponds to hemidesmosomes in Caco-2 cells.
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