In vivo regulation of integrin turnover by outside-in activation

Abstract

The development of three-dimensional tissue architecture requires precise control over the attachment of cells to the extracellular matrix (ECM). Integrins, the main ECM-binding receptors in animals, are regulated in multiple ways to modulate cell-ECM adhesion. One example is the conformational activation of integrins by extracellular signals (“outside-in activation”) or by intracellular signals (“inside-out activation”), while another is the modulation of integrin turnover. We demonstrate that outside-in activation regulates integrin turnover to stabilize tissue architecture in vivo. Treating fly embryos with Mg2+ and Mn2+, known to induce outside-in activation, resulted in decreased integrin turnover. Mathematical modeling combined with mutational analysis provides mechanistic insight into the stabilization of integrins at the membrane. We show that as tissues mature, outside-in activation is crucial for regulating the stabilization of integrin-mediated adhesions. This data identifies a novel in vivo role for outside-in activation and sheds light on the key transition between tissue morphogenesis and maintenance.