Daniel Julio Lew
James B. Duke Distinguished Professor of Pharmacology and Cancer Biology

Our research interests focus on the control of cell polarity.  Cell polarity is a nearly universal feature of eukaryotic cells. A polarized cell usually has a single, clear axis of asymmetry: a “front” and a “back”.  In the past several years it has become apparent that the highly conserved Rho-family GTPase Cdc42, first discovered in yeast, is a component of a master pathway, employed time and again to promote polarity in different contexts.  

Most cells know which way to polarize.  Concentration gradients of attractants, repellents, nutrients, or pheromones reveal the optimal directions for successful attack, escape, feeding, or mating. However, cells can and do polarize even when deprived of directional cues, choosing a random axis and committing to it as if they knew where they were going.  This process, called "symmetry breaking", reflects the presence of a core internal polarity program.  Our work has uncovered the biochemical basis for this core program, which uses positive feedback loops to reinforce inequalities in the local concentrations of polarity factors, so that stochastic fluctuations are amplified into a single dominating asymmetry.  

We use the tractable budding yeast as a model system.  Because the genes and processes we study are highly conserved, we anticipate that learning the answers to fundamental questions in yeast will be relevant and informative for a wide range of organisms.  Our work combines molecular genetics, cell biology, and mathematical modeling, and addresses questions including:

  • Why is there one and only one “front”?   
  • How is polarity turned on and off?   
  • How does Cdc42 organize the cytoskeleton?  
  • How is polarity guided by pheromone gradients?  

 

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