Necl-5/Poliovirus Receptor Interacts With VEGFR2 and Regulates VEGF-Induced Angiogenesis

Abstract

Rationale: Vascular endothelial growth factor (VEGF), a major proangiogenic agent, exerts its proangiogenic action by binding to VEGF receptor 2 (VEGFR2), the activity of which is regulated by direct interactions with other cell surface proteins, including integrin ␣ V ␤ 3 . However, how the interaction between VEGFR2 and integrin ␣ V ␤ 3 is regulated is not clear. Objective:To investigate whether Necl-5/poliovirus receptor, an immunoglobulin-like molecule that is known to bind integrin ␣ V ␤ 3 , regulates the interaction between VEGFR2 and integrin ␣ V ␤ 3 , and to clarify the role of Necl-5 in the VEGF-induced angiogenesis. Key Words: cell adhesion molecules Ⅲ angiogenesis Ⅲ peripheral vascular disease A ngiogenesis plays an important role in diverse developmental, physiological, and pathological processes. Angiogenesis is triggered by the interaction of proangiogenic growth factors and extracellular matrix with their receptors. Vascular endothelial growth factor (VEGF) is a major proangiogenic agent that regulates multiple key steps of angiogenesis. VEGF exerts its proangiogenic action by binding to VEGF receptor 2 (VEGFR2). The activity of VEGFR2 is regulated by direct interactions with other cell surface proteins, such as coreceptor neuropilins 1 and adhesion molecules, including VE-cadherin 2 and integrins. 3 Integrins, including integrin ␣ V ␤ 3 , are critically involved in angiogenesis and initiate signals that control cell migration, proliferation, and survival. 4 Receptors such as VEGFR2 and plateletderived growth factor (PDGF) receptor (PDGFR) interact with integrins, and these interactions exhibit synergistic effects and cooperatively regulate diverse intracellular signals that control key cell functions. 3,5,6 However, how the interaction between VEGFR2 and integrin ␣ V ␤ 3 through their extracellular regions is regulated is not known. Methods and Results:Original received September 15, 2011; revision received January 12, 2012; accepted January 18, 2012. In December 2011 Nectins and nectin-like molecules (Necls) are immunoglobulinlike cell adhesion molecules that are essential for the formation of cell-cell adhesions, and these molecules regulate a variety of cellular functions, including cell polarization, differentiation, movement, proliferation, and survival. 7,8 Necls comprise a family with 5 members, Necl-1 to -5, and among these, Necl-5 exhibits distinctive expression profiles. Necl-5 was originally identified as human poliovirus receptor (PVR), also termed CD155, 9,10 and as rodent Tage4, which is overexpressed in rodent colon carcinoma. 11,12 Necl-5 is expressed ubiquitously, but its expression level is extremely low in most adult organs in rodents. 13,14 However, it becomes upregulated in the developing or regenerating liver 15,16 and transformed cells. 17,18 In NIH3T3 cells, Necl-5 forms a complex with integrin ␣ V ␤ 3 and PDGFR, and the formation of this complex enhances cell movement and proliferation. 19 However, the function of Necl-5 and its mode of action in vascular endothelial ...

Nectin-Like Molecule-5 Regulates Intimal Thickening After Carotid Artery Ligation in Mice

“…Necl-5 enhances the migration and proliferation of NIH3T3 cells 27 and endothelial cells. 26 Consistent with these previous studies, Necl-5 enhanced the migration and proliferation of SMCs. In NIH3T3 cells, Necl-5 interacts with sprouty2, a protein that inhibits the Ras/ERK signaling pathway, 38,39 and prevents the tyrosine phosphorylation and activation of sprouty2.…”

“…Necl-5 is involved in various pathophysiological processes, given that it is overexpressed in the regenerating liver after injury, 22,23 hindlimbs after femoral artery ligation, 26 and cancer cells. 31,32 The expression of Necl-5 is regulated by the Ras-ERK-activator protein 1 pathway.…”

“…26 Necl-5 forms a complex with integrin α v β 3 and growth factor receptors, such as plateletderived growth factor receptor and vascular endothelial growth factor receptor, to enhance the migration and proliferation of fibroblasts and endothelial cells. 26,27 In a previous study on endothelial cells, 26 we noticed that Necl-5 is expressed in vascular SMCs in mice. However, the role of Necl-5 in vascular SMCs is unknown.…”

Endothelial SCUBE2 Interacts With VEGFR2 and Regulates VEGF-Induced Angiogenesis

“…For instance, deficiency of a neuropilin-related transmembrane 25 or an immunoglobulin-like cell adhesion molecule 26 in mice did not affect embryonic vascular formation but impaired postnatal angiogenesis after ischemia. Although why the absence of these genes is not compensated in ischemia-induced adulthood angiogenesis is unknown, we noted that SCUBE2 but not SCUBE1 or 3 was specifically upregulated by HIF-1α in HUVECs under hypoxia (Figure 2).…”

The role of nectins in different types of cell–cell adhesion

“…Necl-5 is localized at the leading edge of moving cells and forms a complex with integrin avb3 and either platelet-derived growth factor receptor (PDGFR), in NIH3T3 cells (Amano et al, 2008;Ikeda et al, 2004;Minami et al, 2007), or vascular endothelial growth factor receptor (VEGFR), in human umbilical endothelial cells (Kinugasa et al, 2012). These complexes regulate the signals that are initiated by small G-proteins, including Rap, Rac and Rho, and thereby affect cell movement (Amano et al, 2008;Ikeda et al, 2004;Minami et al, 2007;Takahashi et al, 2008).…”