Cytomechanical Systems Integration in Directed Cell Migration

Abstract

The ability of tissue cells to directionally move is critical to development, the immune response and wound healing, and its regulation is compromised in metastatic cancer and vascular disease. Cells move directionally by a repeating cycle of protrusion of the cell edge in the direction of migration, formation of adhesion of the protrusion to the extracellular matrix, pulling against the adhesion for translocation of the cell body, and dissolution of adhesion sites at the trailing edge of the cell to allow advance. This necessitates complex and dynamic mechanical interactions between the cell and its extracellular environment that must be coordinated in space and time by physical and biochemical signals. Mechanical cell outputs are mediated in large part by the cytoskeletal systems, actin and microtubules, but also likely involve contributions from other organelle systems in the cell. Our lab uses quantitative microscopy of protein dynamics in living cells and in vitro biochemistry to understand how cytomechanical systems are integrated to promote the morphogenic activities that drive directed cell movement. We aim to understand how the microtubule and actin cytoskeletons interact to polarize a cell, how the actin cytoskeleton builds specific machines for distinct functions in cell migration, and how the acto-myosin contractile system interfaces with the extracellular matrix via focal adhesions to generate traction force. To aid our studies, we pioneered a method called quantitative Fluorescent Speckle Microscopy (qFSM), which allows quantitative analysis of the dynamics of and interactions between proteins within macromolecular assemblies such as the cytoskeleton and focal adhesions in living cells.