Daniel Lew

Overview:

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?  

 

Positions:

James B. Duke Distinguished Professor of Pharmacology and Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Professor of Pharmacology and Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Professor in Molecular Genetics and Microbiology

Molecular Genetics and Microbiology
School of Medicine

Professor of Cell Biology

Cell Biology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 1990

Rockefeller University

Grants:

Studies of cell polarity, chemotropism, and cell-cycle control

Administered By
Pharmacology & Cancer Biology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Studies of cell polarity, chemotropism, and cell-cycle control

Administered By
Pharmacology & Cancer Biology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Program to Support Student Development and Diversity in Duke Biosciences

Administered By
School of Medicine
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Mechanisms of cell fusion during mating in Saccharomyces cerevisiae

Administered By
Pharmacology & Cancer Biology
Awarded By
Burroughs Wellcome Fund
Role
Principal Investigator
Start Date
End Date

Spatiotemporal modeling of signal transduction in yeast

Administered By
Pharmacology & Cancer Biology
Awarded By
University of North Carolina - Chapel Hill
Role
Principal Investigator
Start Date
End Date

Publications:

Mechanism of commitment to a mating partner in Saccharomyces cerevisiae.

Many cells detect and follow gradients of chemical signals to perform their functions. Yeast cells use gradients of extracellular pheromones to locate mating partners, providing a tractable model for understanding how cells decode the spatial information in gradients. To mate, yeast cells must orient polarity toward the mating partner. Polarity sites are mobile, exploring the cell cortex until they reach the proper position, where they stop moving and "commit" to the partner. A simple model to explain commitment posits that a high concentration of pheromone is detected only upon alignment of partner cells' polarity sites and causes polarity site movement to stop. Here we explore how yeast cells respond to partners that make different amounts of pheromone. Commitment was surprisingly robust to various pheromone levels, ruling out the simple model. We also tested whether adaptive pathways were responsible for the robustness of commitment, but our results show that cells lacking those pathways were still able to accommodate changes in pheromone. To explain this robustness, we suggest that the steep pheromone gradients near each mating partner's polarity site trap the polarity site in place.
Authors
Jacobs, KC; Gorman, O; Lew, DJ
MLA Citation
Jacobs, Katherine C., et al. “Mechanism of commitment to a mating partner in Saccharomyces cerevisiae.Mol Biol Cell, vol. 33, no. 12, Oct. 2022, p. ar112. Pubmed, doi:10.1091/mbc.E22-02-0043.
URI
https://scholars.duke.edu/individual/pub1532260
PMID
35947501
Source
pubmed
Published In
Molecular Biology of the Cell
Volume
33
Published Date
Start Page
ar112
DOI
10.1091/mbc.E22-02-0043

Targeted secretion: Myosin V delivers vesicles through formin condensates.

Secretory vesicles are often delivered to very specific targets, like pre-synaptic terminals or cell tips, to focus exocytosis. New work suggests that a biomolecular condensate focuses actin filaments that deliver incoming vesicles through the condensate to the plasma membrane.
Authors
Jacobs, KC; Gladfelter, AS; Lew, DJ
MLA Citation
Jacobs, Katherine C., et al. “Targeted secretion: Myosin V delivers vesicles through formin condensates.Curr Biol, vol. 32, no. 21, Nov. 2022, pp. R1228–31. Pubmed, doi:10.1016/j.cub.2022.10.001.
URI
https://scholars.duke.edu/individual/pub1555951
PMID
36347230
Source
pubmed
Published In
Curr Biol
Volume
32
Published Date
Start Page
R1228
End Page
R1231
DOI
10.1016/j.cub.2022.10.001

Cultivating PhD Aspirations during College.

Science, technology, engineering, and mathematics (STEM) career barriers persist for individuals from marginalized communities due to financial and educational inequality, unconscious bias, and other disadvantaging factors. To evaluate differences in plans and interests between historically underrepresented (UR) and well-represented (WR) groups, we surveyed more than 3000 undergraduates enrolled in chemistry courses. Survey responses showed all groups arrived on campus with similar interests in learning more about science research. Over the 4 years of college, WR students maintained their interest levels, but UR students did not, creating a widening gap between the groups. Without intervention, UR students participated in lab research at lower rates than their WR peers. A case study pilot program, Biosciences Collaborative for Research Engagement (BioCoRE), encouraged STEM research exploration by undergraduates from marginalized communities. BioCoRE provided mentoring and programming that increased community cohesion and cultivated students' intrinsic scientific mindsets. Our data showed that there was no statistical significant difference between BioCoRE WR and UR students when surveyed about plans for a medical profession, graduate school, and laboratory scientific research. In addition, BioCoRE participants reported higher levels of confidence in conducting research than non-BioCoRE Scholars. We now have the highest annual number of UR students moving into PhD programs in our institution's history.
Authors
Jones, DS; Gillette, DD; Cooper, PE; Salinas, RY; Hill, JL; Black, SJ; Lew, DJ; Canelas, DA
MLA Citation
Jones, Daniela S., et al. “Cultivating PhD Aspirations during College.Cbe Life Sci Educ, vol. 21, no. 2, June 2022, p. ar22. Pubmed, doi:10.1187/cbe.20-06-0111.
URI
https://scholars.duke.edu/individual/pub1513631
PMID
35324271
Source
pubmed
Published In
Cbe Life Sciences Education
Volume
21
Published Date
Start Page
ar22
DOI
10.1187/cbe.20-06-0111

Orientation of Cell Polarity by Chemical Gradients.

Accurate decoding of spatial chemical landscapes is critical for many cell functions. Eukaryotic cells decode local chemical gradients to orient growth or movement in productive directions. Recent work on yeast model systems, whose gradient sensing pathways display much less complexity than those in animal cells, has suggested new paradigms for how these very small cells successfully exploit information in noisy and dynamic pheromone gradients to identify their mates. Pheromone receptors regulate a polarity circuit centered on the conserved Rho-family GTPase, Cdc42. The polarity circuit contains both positive and negative feedback pathways, allowing spontaneous symmetry breaking and also polarity site disassembly and relocation. Cdc42 orients the actin cytoskeleton, leading to focused vesicle traffic that promotes movement of the polarity site and also reshapes the cortical distribution of receptors at the cell surface. In this article, we review the advances from work on yeasts and compare them with the excitable signaling pathways that have been revealed in chemotactic animal cells.
Authors
Ghose, D; Elston, T; Lew, D
MLA Citation
Ghose, Debraj, et al. “Orientation of Cell Polarity by Chemical Gradients.Annu Rev Biophys, vol. 51, May 2022, pp. 431–51. Pubmed, doi:10.1146/annurev-biophys-110821-071250.
URI
https://scholars.duke.edu/individual/pub1521654
PMID
35130037
Source
pubmed
Published In
Annu Rev Biophys
Volume
51
Published Date
Start Page
431
End Page
451
DOI
10.1146/annurev-biophys-110821-071250

Pheromone Guidance of Polarity Site Movement in Yeast.

Cells' ability to track chemical gradients is integral to many biological phenomena, including fertilization, development, accessing nutrients, and combating infection. Mating of the yeast Saccharomyces cerevisiae provides a tractable model to understand how cells interpret the spatial information in chemical gradients. Mating yeast of the two different mating types secrete distinct peptide pheromones, called a-factor and α-factor, to communicate with potential partners. Spatial gradients of pheromones are decoded to guide mobile polarity sites so that polarity sites in mating partners align towards each other, as a prerequisite for cell-cell fusion and zygote formation. In ascomycetes including S. cerevisiae, one pheromone is prenylated (a-factor) while the other is not (α-factor). The difference in physical properties between the pheromones, combined with associated differences in mechanisms of secretion and extracellular pheromone metabolism, suggested that the pheromones might differ in the spatial information that they convey to potential mating partners. However, as mating appears to be isogamous in this species, it is not clear why any such signaling difference would be advantageous. Here we report assays that directly track movement of the polarity site in each partner as a way to understand the spatial information conveyed by each pheromone. Our findings suggest that both pheromones convey very similar information. We speculate that the different pheromones were advantageous in ancestral species with asymmetric mating systems and may represent an evolutionary vestige in yeasts that mate isogamously.
Authors
Jacobs, KC; Lew, DJ
MLA Citation
Jacobs, Katherine C., and Daniel J. Lew. “Pheromone Guidance of Polarity Site Movement in Yeast.Biomolecules, vol. 12, no. 4, Mar. 2022. Pubmed, doi:10.3390/biom12040502.
URI
https://scholars.duke.edu/individual/pub1515388
PMID
35454091
Source
pubmed
Published In
Biomolecules
Volume
12
Published Date
DOI
10.3390/biom12040502

Research Areas:

Actin Cytoskeleton
Adaptor Proteins, Signal Transducing
CDC28 Protein Kinase, S cerevisiae
Cell Cycle
Cell Division
Cell Polarity
Cell Shape
Cell Wall
Chemotaxis
Computer Simulation
Cyclin B
Cyclin-Dependent Kinases
Cyclins
Cytokinesis
Cytoskeleton
Feedback, Physiological
Fluorescence Recovery After Photobleaching
GTP-Binding Proteins
GTPase-Activating Proteins
Guanine Nucleotide Exchange Factors
MAP Kinase Signaling System
Microscopy, Confocal
Mitogen-Activated Protein Kinases
Morphogenesis
Phosphothreonine
Polarity
Protein Kinases
Saccharomyces cerevisiae
Saccharomyces cerevisiae Proteins
Septins
Signal Transduction
Systems Biology
Time-Lapse Imaging
Yeast
cdc42 GTP-Binding Protein
cdc42 GTP-Binding Protein, Saccharomyces cerevisiae
p21-Activated Kinases