Defining the mechanism of integrin receptor agonism and efficacy. (360G-Wellcome-074941_Z_04_A)

Adhesion receptor signalling is essential for maintaining tissue structure and controlling cell migration. Conversely, dysregulation of adhesion contributes to the progression of a wide range of diseases by disrupting tissue architecture and allowing aberrant cell trafficking. To mediate these functions, adhesion receptors (principally integrins and syndecans) control dynamic interactions between extracellular matrices and the contractile cytoskeleton. In cultured cells, sites of cell-extracellular matrix contact are elaborated as focal assemblies of cytoskeletal and signalling molecules. These adhesion contacts are created, mature and dissolve as cells make and break contact with their environment. A long-standing challenge in the field is to understand how adhesion receptors convert ligand binding into the efficacious signals that regulate cell movement. By focusing on the mechanisms that determine receptor activation, the signalling events that coordinate the functions of different receptors, and the relationship between receptor activation and adhesion contact maturation, we aim to obtain a holistic understanding of adhesion signalling. We will employ fibroblast and melanoma cells model systems, and focus on the mechanisms of action of three fibronectin receptors: the a4ß1 and a5ß1 integrins, and syndecan-4. Specifically, we will: 1. Determine the structural basis of integrin priming and ligand activation by: Defining the intramolecular mechanisms of integrin activation induced by point mutations and stimulatory monoclonal antibodies. Solving the structure of different integrin activation state classes. 2. Elucidate the molecular basis of adhesion receptor cross-talk by: Defining the mechanisms of integrin/syndecan-interdependent Rho family GTPase regulation. Delineating the signalling events that determine integrin-specific modulation of the cytoskeleton. 3. Define the dynamic changes in adhesion contacts that integrate adhesion and migration by: Elucidating the linkage between integrin conformation and adhesion contact composition. Analysing the temporal segregation of cytoskeletal components during adhesion contact maturation.