Localization of nectin-free afadin at the leading edge and its involvement in directional cell movement induced by platelet-derived growth factor

Abstract

for the recruitment of afadin and the tyrosine phosphatase SHP-2 to the leading edge. SHP-2 was previously reported to tightly regulate the activation of PDGF receptor and its downstream signaling pathway for the formation of the leading edge. These results indicate that afadin has a novel role in PDGF-induced directional cell movement, presumably in cooperation with active Rap1 and SHP-2.Supplementary material available online at

Role of Scaffold Protein Afadin Dilute Domain-interacting Protein (ADIP) in Platelet-derived Growth Factor-induced Cell Movement by Activating Rac Protein through Vav2 Protein

“…In addition to integrin ␣v␤3, the cell-cell adhesion molecule occludin and the scaffold proteins IQGAP and vinculin have been reported to regulate both cell movement and cell-cell junctions (40 -44). Our previous and present data also demonstrate that afadin and ADIP are involved in cell movement and cell-cell junctions (13,19,45). For the physiological regulation of mesenchymal-epithelial transition and epithelial-mesenchymal transition, it may be advantageous that some molecules mutually function in cell movement and cell-cell junctions.…”

“…Afadin enhances the activation of Rac through Vav2 and inhibits the activation of RhoA through ARAP1, a GTPase-activating protein for RhoA (16), whereas ADIP only mediates the activation of Rac. Afadin regulates the PDGF-induced, Crk-and C3G-mediated activation of Rap1 and directly interacts with activated Rap1 to stabilize the localization of the ternary complex containing PDGF receptor, integrin ␣v␤3, and Necl-5 at the leading edge (13,16), whereas ADIP has no effect on the activation of Rap1. Thus, afadin and ADIP play distinct roles in the intracellular signaling for cell movement, although these proteins co-localize at the leading edge and are reported to directly interact with each other (19).…”

“…Stimulation-Previously, we reported that afadin is important for the formation of the leading edge in moving cells and that afadin interacts with ADIP at AJs (13,16,19,29). Based on these results, we first examined whether ADIP is concentrated at the leading edge of moving cells.…”

“…In a previous study, we demonstrated that nectin-like molecule 5 (Necl-5), 2 an immunoglobulin-like cell adhesion molecule, forms a ternary complex with PDGF receptor and integrin ␣v␤3 at the leading edge and enhances the PDGF-induced cell movement (11,12). More recently, we also clarified that the accumulation and stabilization of the ternary complex at the leading edge are controlled by afadin (13). Afadin was identified as an actin filament (F-actin)-binding protein that localizes at cell-cell adherens junctions (AJs; Ref.…”

Cooperative Role of Nectin-Nectin and Nectin-Afadin Interactions in Formation of Nectin-based Cell-Cell Adhesion

“…In addition to the role of afadin in cell-cell adhesion, afadin is involved in directional cell movement (4,5). It was shown previously that the PDGF receptor and integrin ␣ v ␤ 3 cooperatively induce movement of NIH3T3 cells (6).…”