Many eukaryotic cells have the capacity to polarize and migrate in response to external gradients of chemoattractant. Directed motility is essential for single-celled organisms to hunt and mate, axons to find their way in the developing nervous system, and cells in the innate immune system to find and kill invading pathogens. We are just beginning to understand the circuitry of the internal 'compass' used by eukaryotic cells to regulate polarity during chemotaxis. However, many of the important connections are missing and we lack a mechanistic understanding of how the known regulators interact to process spatial signals and coordinate the many activities involved in directed cell migration. Our research focuses on identifying these key missing components and how the overall signaling network is wired together to produce appropriately oriented cell polarity. Our favorite material for these studies are neutrophils (one of nature's master migratory cells) and neutrophil lysates, which contain massive concentrations of many polarity components.
Figure 1. Human neutrophil (from my finger) polarizing in response to gradient of chemoattractant.
Biochemistry and genetics have given us some of the linear connections from chemoattractant receptors to the cytoskeleton, but this linear cascade does not explain polarity. Cell polarity exists as a consequence of the positive and negative feedback loops and cross-pathway modulations that are superimposed on these primary circuits. These higher order feedback loops allow for the fascinating self-organizing properties of cell polarity. We recently discovered a Rac and PI3Kinase positive feedback loop that may act through a self-organizing pattern formation system to regulate cell polarity. This circuit may constitute a broadly conserved module for the establishment of cell polarity during eukaryotic chemotaxis, but we are missing several essential players.
Part of our research focuses on discovering new components of the chemotactic compass, and this approach has successfully identified an essential polarity scaffold. This scaffold is required for the structural and biochemical organization of the leading edge and plays a key role in myosin regulation and the PIP3/Rac/actin positive feedback loop that regulates cell polarity. This scaffold may regulate an entire program of polarity effectors that act at the leading edge during chemotaxis.
We are also developing technologies to provide a better understanding of how these pieces work together to produce polarity. We have made significant progress towards reconstituting key polarity circuits in vitro , developing a biochemically accessible system for the entire polarity cascade, and testing how these components spatially orchestrate polarity. Taking this complex machine apart, putting the pieces back together, and manipulating activities in the cell in a highly controlled fashion will give us a much more rigorous understanding of how these amazing little cells work. |
Biomedical Sciences (BMS) Graduate Program
