Our research interests encompass questions on cell cycle control, the control of cell polarity, and the specification of distinct cortical domains within cells. We are also trying to understand how cells can monitor their shape and react to environmental influences that affect cytoskeletal behavior.
One focus is the study of how the Cyclin Dependent Kinases (CDKs) that control cell cycle progression act to promote specific changes in cell polarity. A ras-related G protein, Cdc42p, is key for enacting changes in cell polarity involving reorganization of both actin and septins (a poorly understood filamentous system that specializes specific cortical domains) in response to CDK activity. We are tracing the links between the CDK and Cdc42p to understand how polarity is established, and the links between Cdc42p and the cytoskeleton to determine how polarized behavior is executed.
A second focus involves investigation of a cell cycle checkpoint control that monitors cell shape. When environmental insults disrupt cytoskeletal organization, this checkpoint delays entry into mitosis through inhibition of CDK/cyclin kinases. A tyrosine kinase, Swe1p, is responsible for the cell cycle block, and we have found that the degradation of Swe1p is regulated both by cell shape and by perturbation of the actin cytoskeleton. Recently, we discovered that the septin cytoskeleton is directly affected by local cell shape, and that proteins controlling Swe1p degradation can monitor this septin change.
The biological problems we address are universal, and the proteins that we study are widely conserved. We have chosen the experimentally tractable budding yeast as our experimental system and are using genetic, cell biological, and biochemical approaches to study these pathways.
Daniel Lew obtained a BA in genetics from Cambridge University (UK), and then a PhD in molecular biology working with James Darnell on interferon-stimulated transcription at the Rockefeller University (NY). After postdoctoral training on yeast genetics and cell cycle control with Steve Reed at the Scripps Research Institute (CA), he joined the Duke University faculty in 1994. His work has focused on the control of the cell cycle by cell shape and cytoskeletal stress, and on polarity establishment, with a view to understanding the universal problems of symmetry breaking and singularity (i.e. why a polarized cell has one and only one “front”). His group combines mathematical modeling with genetics/biochemistry/cell biology approaches to understand the design principles of the polarity machinery, and more recently the basis for effective tracking of pheromone gradients. He is currently a James B. Duke Professor of Pharmacology and Cancer Biology.