Interaction of Necl‐4/CADM4 with ErbB3 and integrin α₆β₄ and inhibition of ErbB2/ErbB3 signaling and hemidesmosome disassembly

Abstract

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 a 6 b 4 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.

Cadm4 Restricts the Production of Cardiac Outflow Tract Progenitor Cells

“…Further evaluation of this model will benefit from examining where and when interactions between Cadm family members occur in the distal territory; in this regard, it is intriguing that cadm2a , like cadm4 , is upregulated in SU5402-treated embryos (Table S1). Alternatively, Cadm4 may influence OFT progenitor production through interactions with other signaling pathways; in cell culture, for example, Cadm4 has been shown to interact in cis with ErbB receptors (Sugiyama et al, 2013). …”

A Novel Nectin-mediated Cell Adhesion Apparatus That Is Implicated in Prolactin Receptor Signaling for Mammary Gland Development

“…We previously showed physical and functional interactions between the nectin and nectin-like molecule (Necl) family proteins and receptors, such as nectin-3 and the PDGF receptor, Necl-5 and the PDGF receptor, Necl-2 and ErbB3, Necl-4 and ErbB3, Necl-4 and the VEGF receptor, and Necl-5 and the VEGF receptor (26,(42)(43)(44)(45)(46). Most of these studies were done in transfected cell lines overexpressing these proteins, and it still remains unknown whether these interactions are direct or indirect.…”

Clinicopathological significance of Necl-4 expression in pancreatic ductal adenocarcinoma

“…Necl-4 has been reported to act as a tumour suppressor in several types of cancer 7 8 14. On analysis of Necl-4 tumour suppressor activity in nude mice between PPC-1 prostate cancer cells transfected with Necl-4, parental PPC-1 cells, and PPC-1 cells transfected with a control plasmid, only 37% of the sites injected with Necl-4-transfected PPC-1 cells developed notable tumours compared with 100% of the sites injected with parental or control-transfected PPC-1 cells.…”

“…Several molecular mechanisms have been proposed to support a tumour-suppressive role for Necl-4 in human malignancies. Necl-4 serves as a tumour suppressor by inhibiting ErbB2/ErbB3 signalling and hemidesmosome disassembly 8. Necl-4 also serves as a novel regulator for contact inhibition of cell movement and proliferation in cooperation with vascular endothelial growth factor receptor and protein-tyrosine phosphatase, non-receptor type 13 17.…”

“…Necl-4 regulates contact inhibition of cell movement and proliferation cooperatively with the vascular endothelial growth factor receptor and protein-tyrosine phosphatase, non-receptor type 13 17. Furthermore, Necl-4 serves as a tumour suppressor by inhibiting ErbB2/ErbB3 signalling and hemidesmosome disassembly and by enhancing apoptosis 8 13…”