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.
Highlights
Contact inhibition of cell movement and proliferation is essential for proper morphogenesis and maintenance of tissue architecture during embryonic development and regeneration in adults [1,2]
We have shown that another family of cell adhesion molecule (CAM) nectins, consisting of four members, regulate cell—cell adhesion, cell movement, and cell proliferation in various types of cells [8,9]
We have identified nectinlike molecule-5 (Necl-5), a member of the Necl family of proteins consisting of five members (Necl-1 to Necl-5), as the third regulatory factor for cell movement and proliferation, in addition to growth factor receptors and integrins [10]
Summary
Contact inhibition of cell movement and proliferation is essential for proper morphogenesis and maintenance of tissue architecture during embryonic development and regeneration in adults [1,2]. Deregulation of contact inhibition is thought to play a role in tumorigenesis. Contact inhibition is a phenomenon that can be observed between two moving and proliferating cells in culture. They gradually reduce movement and proliferation, and eventually stop moving and proliferating [1,2]. To understand the molecular mechanisms underlying the contact inhibition, the molecular mechanisms for cell—cell adhesion, cell movement, cell proliferation, and mutual interactions among these three cellular responses have.
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