The Cell Adhesion Molecule Necl-4/CADM4 Serves as a Novel Regulator for Contact Inhibition of Cell Movement and Proliferation

PLoS One. 2015 Apr 20;10(4):e0124259. doi: 10.1371/journal.pone.0124259. eCollection 2015.

Abstract

Contact inhibition of cell movement and proliferation is critical for proper organogenesis and tissue remodeling. We show here a novel regulatory mechanism for this contact inhibition using cultured vascular endothelial cells. When the cells were confluently cultured, Necl-4 was up-regulated and localized at cell-cell contact sites where it cis-interacted with the vascular endothelial growth factor (VEGF) receptor. This interaction inhibited the tyrosine-phosphorylation of the VEGF receptor through protein-tyrosine phosphatase, non-receptor type 13 (PTPN13), eventually reducing cell movement and proliferation. When the cells were sparsely cultured, Necl-4 was down-regulated but accumulated at leading edges where it inhibited the activation of Rho-associated protein kinase through PTPN13, eventually facilitating the VEGF-induced activation of Rac1 and enhancing cell movement. Necl-4 further facilitated the activation of extracellular signal-regulated kinase 1/2, eventually enhancing cell proliferation. Thus, Necl-4 serves as a novel regulator for contact inhibition of cell movement and proliferation cooperatively with the VEGF receptor and PTPN13.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Adhesion Molecules / metabolism*
  • Cell Communication
  • Cell Movement
  • Cell Proliferation
  • Cells, Cultured
  • Collagen / chemistry
  • Drug Combinations
  • Gene Expression Regulation*
  • Human Umbilical Vein Endothelial Cells / cytology
  • Humans
  • Immunoglobulins / metabolism*
  • Laminin / chemistry
  • Phosphorylation
  • Protein Tyrosine Phosphatase, Non-Receptor Type 13 / metabolism*
  • Proteoglycans / chemistry
  • RNA, Small Interfering / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Shelterin Complex
  • Telomere-Binding Proteins / metabolism
  • Vascular Endothelial Growth Factor A / metabolism*
  • Vascular Endothelial Growth Factor Receptor-1 / metabolism
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism
  • Wound Healing

Substances

  • CADM4 protein, human
  • Cell Adhesion Molecules
  • Drug Combinations
  • Immunoglobulins
  • Laminin
  • Proteoglycans
  • RNA, Small Interfering
  • Shelterin Complex
  • TERF2IP protein, human
  • Telomere-Binding Proteins
  • Vascular Endothelial Growth Factor A
  • matrigel
  • Collagen
  • KDR protein, human
  • Vascular Endothelial Growth Factor Receptor-1
  • Vascular Endothelial Growth Factor Receptor-2
  • PTPN13 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 13

Grants and funding

This study was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (https://www.jsps.go.jp/english/e-grants) (to YT (21227005) and YR (25461128)) and by grants from the Global Center of Excellence (http://www.jsps.go.jp/english/e-globalcoe) (to SY, KH, YR), the Takeda Science Foundation (http://www.takeda-sci.or.jp), the Naito Foundation (https://www.naito-f.or.jp), and the SENSHIN Medical Research Foundation (http://www.mt-pharma.co.jp/zaidan) (to YR). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.