Nectin-like molecule 4 (Necl-4)/CADM4, a transmembrane cell-cell adhesion molecule with three Ig-like domains, was shown to serve as a tumor suppressor, but its mode of action has not been elucidated. In this study, we showed that Necl-4 interacted in cis with ErbB3 through their extracellular regions, recruited PTPN13 and inhibited the heregulin-induced activation of the ErbB2/ErbB3 signaling. In addition, we extended our previous finding that Necl-4 interacts in cis with integrin α6β4 through their extracellular regions and found that Necl-4 inhibited the phorbol ester-induced disassembly of hemidesmosomes. These results indicate that Necl-4 serves as a tumor suppressor by inhibiting the ErbB2/ErbB3 signaling and hemidesmosome disassembly.
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