"Integrin-mediated cell adhesion is essential for the development and homeostasis of multicellular organisms. Integrins are ubiquitously expressed heterodimeric adhesion receptors consisting of α and β subunits. They exhibit two striking properties; they can regulate their affinity for ligands and assemble large signalling hubs called adhesomes. Both properties depend on the α and β cytoplasmic tails; when integrins switch from inactive to active conformations their weakly associated tails separate and recruit adhesion proteins leading to adhesome assembly. How active integrins revert to the inactive state, and how the weak α/β tail association is maintained is largely unknown. The mechanistic contribution of individual integrin classes to the recruitment of proteins to the adhesome and how adhesome signalling is induced is also unclear. In this proposal we will address these fundamental questions in 4 specific aims. In the first aim we will identify proteins that keep integrin tails associated and define the roles of their tail binding with respect to integrin inactivation and turn over. In the second aim we will utilize high-resolution quantitative mass spectrometry to define how different integrins assemble adhesomes with common and specific components that signal in highly regulated manners. Our third aim will determine how integrin tails nucleate an adhesion complex that expedites further interactions with multiple binding partners by performing crosslinking proteomics of adhesion proteins bound to different β integrin tails in vitro. In the fourth aim we will use genetically engineered mice to determine how ubiquitously expressed proteins of the adhesome perform organ- and cell type-specific functions. Completion of these aims will help define the fundamental mechanisms whereby integrins control their complex signalling networks. This has implications for our understanding of development and disease as integrins play key roles for almost all cellular functions."