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
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Adhesion Molecules / metabolism*
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Cell Communication
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Cell Movement
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Cell Proliferation
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Cells, Cultured
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Collagen / chemistry
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Drug Combinations
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Gene Expression Regulation*
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Human Umbilical Vein Endothelial Cells / cytology
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Humans
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Immunoglobulins / metabolism*
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Laminin / chemistry
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Phosphorylation
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Protein Tyrosine Phosphatase, Non-Receptor Type 13 / metabolism*
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Proteoglycans / chemistry
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RNA, Small Interfering / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Shelterin Complex
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Telomere-Binding Proteins / metabolism
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Vascular Endothelial Growth Factor A / metabolism*
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Vascular Endothelial Growth Factor Receptor-1 / metabolism
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Vascular Endothelial Growth Factor Receptor-2 / metabolism
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Wound Healing
Substances
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CADM4 protein, human
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Cell Adhesion Molecules
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Drug Combinations
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Immunoglobulins
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Laminin
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Proteoglycans
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RNA, Small Interfering
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Shelterin Complex
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TERF2IP protein, human
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Telomere-Binding Proteins
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Vascular Endothelial Growth Factor A
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matrigel
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Collagen
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KDR protein, human
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Vascular Endothelial Growth Factor Receptor-1
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Vascular Endothelial Growth Factor Receptor-2
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PTPN13 protein, human
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Protein Tyrosine Phosphatase, Non-Receptor Type 13