Abstract

The turnover of integrin receptors is critical for cell migration and adhesion dynamics. Here we find that force development at integrins regulates adaptor protein recruitment and endocytosis. Using mobile RGD (Arg-Gly-Asp) ligands on supported lipid membranes (RGD membranes) and rigid RGD ligands on glass (RGD-glass), we find that matrix force-dependent integrin signals block endocytosis. Dab2, an adaptor protein of clathrin-mediated endocytosis, is not recruited to activated integrin-beta3 clusters on RGD-glass; however, it is recruited to integrin-mediated adhesions on RGD membranes. Further, when force generation is inhibited on RGD-glass, Dab2 binds to integrin-beta3 clusters. Dab2 binding to integrin-beta3 excludes other adhesion-related adaptor proteins, such as talin. The clathrin-mediated endocytic machinery combines with Dab2 to facilitate the endocytosis of RGD-integrin-beta3 clusters. From these observations, we propose that loss of traction force on ligand-bound integrin-beta3 causes recruitment of Dab2/clathrin, resulting in endocytosis of integrins.

Highlights

  • The turnover of integrin receptors is critical for cell migration and adhesion dynamics

  • If no force develops on the cell–matrix interface, activated RGD-integrin-beta[3] clusters fail to form mature adhesions and adhesion-related molecules are replaced by endocytic adaptor proteins, including Dab[2]

  • When cells adhered on mobile RGD membranes, Dab[2] was found at a subpopulation of RGD-integrin-beta[3] clusters (Fig. 1b and Supplementary Fig. 1a)

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Summary

Introduction

The turnover of integrin receptors is critical for cell migration and adhesion dynamics. We find that force development at integrins regulates adaptor protein recruitment and endocytosis. Dab[2], an adaptor protein of clathrin-mediated endocytosis, is not recruited to activated integrin-beta[3] clusters on RGD-glass; it is recruited to integrin-mediated adhesions on RGD membranes. The clathrin-mediated endocytic machinery combines with Dab[2] to facilitate the endocytosis of RGD-integrin-beta[3] clusters. Outside-in integrin activation by extracellular ligand binding initially triggers a series of biochemical reactions, such as the recruitment of adaptor proteins and filamentous actin (F-actin) polymerization that establishes micrometre-sized adhesion clusters[4,5]. If no force develops on the cell–matrix interface, activated RGD-integrin-beta[3] clusters fail to form mature adhesions and adhesion-related molecules are replaced by endocytic adaptor proteins, including Dab[2]

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