Travelling waves of signaling and cytoskeletal events at the cell cortex have emerged as a common phenomenon in diverse cell types, yet the molecular mechanisms and cellular functions are poorly understood. Here I use the model system Dictyostelium to elucidate principles underlying wave self-organization and illuminate the roles of cortical waves in cell migration.
We found that the formation of cortical waves is controlled by two coordinated networks of different time scales: a slow network including Rap/Ras small GTPases, PI3K, and PKB, and a fast one containing Rac small GTPase, F-actin, RacGEF1, and Coronin. These networks displayed hallmarks of excitable media. To illustrate the molecular basis of excitability, I adopted the FKBP-FRB dimerization system for rapid perturbation of wave properties. Acute lowering PIP2 levels or activating Rap/Ras increased the speed and range of waves, elevating PKB activity hindered wave propagation, whereas activating Rac generated unorganized patches of actin polymerization. Linking these observations to a theoretical framework, we mapped the feedback loops within and between the Ras/Rap- and Rac/F-actin- centric networks which together control wave generation.
The same perturbations that shifted wave properties also transformed types of cellular protrusion and modes of cell migration. Innate pseudopodia and macropinosomes of Dictyostelium cells were promptly switched to lamellipodia-like protrusions, once the speed and range of waves were elevated. As a result, amoeboid migratory modes transitioned to gliding keratocyte-like or oscillatory mode. On the other hand, filopodia-like protrusions appeared after actin wave propagation was acutely hindered. Taken together, a causal chain of events is revealed: The thresholds of excitable networks control the speed and range of waves, which organize the size and dynamics of cellular protrusions, which determine different cell migratory modes. These suggest that various types of protrusion are on a continuum and the overall state of the excitable networks determines cell morphology. We advance a unifying theory that wave propagation serves as a higher order organizer of cellular protrusions, which might explain migratory transitions found in development and pathological conditions
