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

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.细胞运动与增殖的接触抑制对正常器官发生及组织重塑至关重要。本研究利用培养的血管内皮细胞（vascular endothelial cells），揭示了该接触抑制现象的全新调控机制。当细胞汇合培养时，Necl-4表达上调并定位于细胞-细胞接触位点，在此处与血管内皮生长因子（vascular endothelial growth factor, VEGF）受体发生顺式相互作用。该相互作用通过非受体型蛋白酪氨酸磷酸酶13（protein-tyrosine phosphatase, non-receptor type 13, PTPN13）抑制VEGF受体的酪氨酸磷酸化，最终减弱细胞运动与增殖能力。当细胞稀疏培养时，Necl-4表达下调，但在细胞前沿富集，在此处通过PTPN13抑制Rho相关蛋白激酶（Rho-associated protein kinase）的激活，最终促进VEGF诱导的Rac1活化并增强细胞运动能力。Necl-4还可进一步促进细胞外调节蛋白激酶1/2（extracellular signal-regulated kinase 1/2）的活化，最终增强细胞增殖能力。综上，Necl-4可与VEGF受体及PTPN13协同作用，作为调控细胞运动与增殖接触抑制的新型调控因子。