 |
Center for Nonlinear Studies |
The past fifteen years have seen a dramatic expansion in our knowledge of signal transduction pathways and networks, which activate and regulate cell functional responses to specific extracellular cues. As a model system, we have studied signaling through the phosphoinositide (PI) 3-kinase pathway, stimulated by platelet-derived growth factor (PDGF) in mouse fibroblasts, which is required for cell proliferation, survival, and directed migration in dermal wound healing. Using a combination of molecular, biochemical, live-cell fluorescence, and modeling/computational techniques, we have studied the mechanisms and kinetics of PDGF receptor activation and formation of PI 3-kinase complexes, the influence of molecular crosstalk from the Ras pathway, and the spatial patterning of 3’ PI density in the membrane. Qualitative insights from these analyses are being incorporated into higher-level models of fibroblast dynamics during invasion of wounded tissue, in which the description of PI 3-kinase signaling is appropriately coarse-grained, as an example of integration spanning the hierarchy of molecules, cells, and tissues. Running throughout is a common theme: the balance that must be struck between the kinetics of the rate-limiting process(es) and transport across the relevant length scale.