DESCRIPTION (provided by applicant): The overall goal of this Program Project is to understand in detail how integrin-mediated adhesions mature and how this process determines signaling outputs. Adhesion maturation is highly dependent on physical forces, whether from endogenous myosin or applied externally through the extracellular matrix. Thus, comparison of normal adhesion ultrastructure and dynamics with responses to applied force will elucidate mechanisms of mechanotransduction. This Program Project will develop a model for mechanotransduction at matrix adhesions that integrates adhesion ultrastructure, biochemical interactions, temporal and spatial dynamics of multiprotein assemblies and signaling networks. We will analyze mechanotransduction in the context of cell migration as an important physiological output of adhesion mechanics and signaling. To achieve this, we have formed a unique team of long-standing collaborators who will implement a multifaceted experimental approach that includes molecular cell biology, biochemistry, biophysical approaches, material science, computational and mathematical analysis, and correlated high-resolution light and electron microscopy.

Matrix adhesions sense their mechanical environment and thereby modulate signals that regulate proliferation, differentiation, migration, and cell death. Shifts in force, therefore, can produce developmental defects and contribute to vascular and chronic inflammatory diseases, tumor formation and metastasis. Despite its importance, the mechanism underlying the transduction of force to biological signal is not understood. Our multifaceted approach will reveal its mechanistic and structural basis.