UC San Diego, Department of Bioengineering

Eukaryotic cells move in response to external stimuli by remodeling their cytoskeleton and their substrate adhesions. The production and spatio-temporal organization of the traction forces exerted by the cell during migration are determined by the orchestrated interactions of actin-directed motors, F-actin regulation, actin crosslinking, motor protein contractility and adhesions. This process is controlled by a complex network of signaling pathways that drives a relatively simple repetitive sequence of mechanical actions coordinated in space and time (motility cycle). We show that, under a wide range of conditions, the length of the cell and the strain energy exchanged with the substrate oscillate in time with an average frequency, f, to which smaller, higher-frequency random fluctuations are superimposed. We also show that during chemotaxis, the cell migration speed is directly proportional to the frequency of the motility cycle. This simple proportionality applies not only to wild-type cells but also to some mutant strains with contractility and adhesion defects. We use conditional and phase statistics as well as Principal Component Analysis (PCA) to integrate all the biochemical and mechanical measurements to obtain the quantitative information needed to connect specific biochemical processes to each of the mechanical events in the motility cycle. We demonstrate that Myosin II is essential not only to the contractility phase of the motility cycle but also to the pseudopod protrusion phase. Furthermore, the spatiotemporal organization of the traction forces depends not only on the contractile action of Myosin II, but more importantly in its actin crosslinking effect. Preliminary results indicate that the existence of periodic oscillations in the spatiotemporal distribution of traction forces and the length of the cell rely on actin polymerization.