An Actin-Based Wave Generator Organizes Cell Motility

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Abstract
Although many of the regulators of actin assembly are known, we do not understand how these components act together to organize cell shape and movement. To address this question, we analyzed the spatial dynamics of a key actin regulator—the Scar/WAVE complex—which plays an important role in regulating cell shape in both metazoans and plants. We have recently discovered that the Hem-1/Nap1 component of the Scar/WAVE complex localizes to propagating waves that appear to organize the leading edge of a motile immune cell, the human neutrophil. Actin is both an output and input to the Scar/WAVE complex: the complex stimulates actin assembly, and actin polymer is also required to remove the complex from the membrane. These reciprocal interactions appear to generate propagated waves of actin nucleation that exhibit many of the properties of morphogenesis in motile cells, such as the ability of cells to flow around barriers and the intricate spatial organization of protrusion at the leading edge. We propose that cell motility results from the collective behavior of multiple self-organizing waves. Many cells guide their movement in response to external cues. This ability is required for single-celled organisms to hunt and mate, enables innate immune cells to seek and destroy pathogens, and is also essential for the development of multicellular organisms. Misregulation of cell migration is intimately involved in atherosclerosis and in cancer metastasis. Although many of the regulators of cell migration are known, we do not understand how these components act together to organize cell shape and movement. We used advanced light microscopy to follow the distribution of a key regulator of cell migration in living cells. We focus on a protein called Hem-1, which is part of a large multimolecular protein complex that regulates cell shape in animals and plants. We found that Hem-1 exhibits complex cycles of activation and inhibition to generate waves of propagating Hem-1 and actin assembly that are similar in mechanism to grass fires or the action potentials used in neuronal signaling. These waves potentially explain many of the complex behaviors of motile cells such as the ability of cells to flow around barriers and the intricate spatial organization of protrusion at the front of moving cells.