How Cells Establish Polarity and Guide Movement

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 only beginning to understand the circuitry of the internal 'compass' used by eukaryotic cells to regulate polarity during chemotaxis. Our research focuses on identifying key missing components of the cellular compass and determining how the overall signaling network is wired together to coordinate the many activities involved in directed cell polarity.  Our model systems for these studies are neutrophils (one of nature's master migratory cells) and neutrophil lysates, which contain very high concentrations of many proteins that regulate polarity.

Figure 1. Human neutrophil (from my finger) polarizing in response to gradient of chemoattractant. 
 
Part of our research focuses on identifying core circuits of cell polarity. We discovered a positive feedback loop involving the GTPase Rac, the lipid PIP₃, and actin polymers that plays a central role in generating neutrophil polarity.   Analogous feedback loops are now known to be essential for polarity in cells ranging from yeast to Dictyostelium to neutrophils.  To uncover novel components of this circuit, we used a combination of classical protein purification and reverse genetics to identify a set of protein complexes (Hem-1 containing complexes) that are essential for the feedback loops that control cell polarity in neutrophils. We suspect this scaffold may orchestrate an entire program of polarity effectors that act at the leading edge during chemotaxis, and we are currently dissecting the inputs and outputs of this essential polarity circuit.

We are developing techniques to deconstruct and reconstitute key polarity circuits in vitro and spatially manipulate and monitor signaling in vivo in our quest to understand how these amazing migratory cells work. This knowledge is essential if we are to ultimately control inflammation, cancer metastasis, and other processes that depend on properly guided cell movement.