Cells are extraordinarily adept at detecting and tracking shallow gradients of chemicals of interest. Micro-organisms track gradients to find food or mates, and similar processes underlie axon guidance in the nervous system, homing of immune cells towards invaders, crawling of repair cells towards wound sites, and guidance of sperm towards the egg during conception. Gradient tracking also contributes to metastasis in cancer, so understanding how cells track shallow chemical gradients is of medical relevance as well as fundamental interest. Upon detecting chemicals through cell-surface receptors, cells either move or grow towards the source of the signal. In many cases, the gradients of diffusible substances are shallow, resulting in minuscule concentration differences across the diameter of small cells. Gradient detection is made even more difficult by the randomness of individual receptor-ligand interactions, which leads to molecular noise that can mask the tiny spatial gradient signal. The mechanisms that allow cells to efficiently track even very shallow gradients despite noise are poorly understood. In this proposal, we use the uniquely tractable yeast model system to investigate these mechanisms. During mating, yeast cells polarize and grow up a gradient of pheromone to find and fuse with opposite-sex partners. We propose to use a combination of cutting-edge microscopy, genetics, and computational modeling to understand how it is that yeast cells track pheromone gradients.

Public Health Relevance

The ability to track chemical gradients is crucial for immune cells to home in on intruders that have invaded our bodies. However, gradient-tracking behavior can turn malignant when cancer cells exploit it to escape a tumor and metastasize to new locations. Thus, a better understanding of how cells track gradients may result in ways to boost the immune system or fight metastatic cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM103870-02
Application #
8656373
Study Section
Molecular and Integrative Signal Transduction Study Section (MIST)
Program Officer
Nie, Zhongzhen
Project Start
2013-05-01
Project End
2017-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Duke University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Durham
State
NC
Country
United States
Zip Code
27705
Kang, Hui; Tsygankov, Denis; Lew, Daniel J (2016) Sensing a bud in the yeast morphogenesis checkpoint: a role for Elm1. Mol Biol Cell 27:1764-75
Ramirez, Samuel A; Raghavachari, Sridhar; Lew, Daniel J (2015) Dendritic spine geometry can localize GTPase signaling in neurons. Mol Biol Cell 26:4171-81
Venkatapurapu, Sai Phanindra; Kelley, Joshua B; Dixit, Gauri et al. (2015) Modulation of receptor dynamics by the regulator of G protein signaling Sst2. Mol Biol Cell 26:4124-34
McClure, Allison W; Lew, Daniel J (2015) To avoid a mating mishap, yeast focus and communicate. J Cell Biol 208:867-8
McClure, Allison W; Minakova, Maria; Dyer, Jayme M et al. (2015) Role of Polarized G Protein Signaling in Tracking Pheromone Gradients. Dev Cell 35:471-82
Kelley, Joshua B; Dixit, Gauri; Sheetz, Joshua B et al. (2015) RGS proteins and septins cooperate to promote chemotropism by regulating polar cap mobility. Curr Biol 25:275-85
Wu, Chi-Fang; Chiou, Jian-Geng; Minakova, Maria et al. (2015) Role of competition between polarity sites in establishing a unique front. Elife 4:
McClure, Allison W; Lew, Daniel J (2014) Cell polarity: netrin calms an excitable system. Curr Biol 24:R1050-2