The overall objective of the four projects in this program of research is to develop and exploit biosensors and image analysis techniques to delineate the mechanisms that control the spatial and temporal activity of Rho GTPases in different biological contexts. In particular, guanine nucleotide exchange factors (GEFs), the upstream activators of Rho GTPases, are thought to promote highly polarized signaling that is capable of generating changes in the shape, movement and organization of cells.
The aim of this project (project 3) is to study GEFs in the context of epithelial morphogenesis and migration. Epithelial morphogenesis and migration drive development in the embryo and regeneration and repair in the adult, while defects underlie a wide spectrum of human diseases and syndromes, notably cancer. Depsite representing very different aspects of cell behavior, morphogenesis and migration share many signaling pathway components, in particular Rho GTPases, but the key feature that distinguishes their respective contributions is their distinct spatial localization. The underlying hypothesis is that the spatial localization and molecular specificity of Rho GTPase signaling pathways are determined by specific GEFs (of which there are 82 in the human genome). The key aims are to: (i) identify and molecularly characterize GEFs involved in the establishment (morphogenesis) and dynamic reorganization (collective migration) of apically localized cell-cell junctions and basally localized cell- matrix adhesions in the human bronchial epithelial cell line, 16HBE, and (ii) use GEF biosensors developed by Hahn and Sondek together with image analysis techniques developed by Danuser to visualize their activity and relationship to GTPase signaling in space and time. It is expected that the project will generate significant new insights into the molecular mechanisms regulating fundamental aspects of epithelial cell behavior.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-IMST-J)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of North Carolina Chapel Hill
Chapel Hill
United States
Zip Code
Woodham, Emma F; Paul, Nikki R; Tyrrell, Benjamin et al. (2017) Coordination by Cdc42 of Actin, Contractility, and Adhesion for Melanoblast Movement in Mouse Skin. Curr Biol 27:624-637
Takano, Tetsuya; Wu, Mengya; Nakamuta, Shinichi et al. (2017) Discovery of long-range inhibitory signaling to ensure single axon formation. Nat Commun 8:33
Zaritsky, Assaf; Obolski, Uri; Gan, Zhuo et al. (2017) Decoupling global biases and local interactions between cell biological variables. Elife 6:
Zaritsky, Assaf; Tseng, Yun-Yu; Rabadán, M Angeles et al. (2017) Diverse roles of guanine nucleotide exchange factors in regulating collective cell migration. J Cell Biol 216:1543-1556
Taylor, A B; Ioannou, M S; Watanabe, T et al. (2017) Perceptually accurate display of two greyscale images as a single colour image. J Microsc 268:73-83
Herrington, Kari A; Trinh, Andrew L; Dang, Carolyn et al. (2017) Spatial analysis of Cdc42 activity reveals a role for plasma membrane-associated Cdc42 in centrosome regulation. Mol Biol Cell 28:2135-2145
Lawson, Campbell D; Fan, Cheng; Mitin, Natalia et al. (2016) Rho GTPase Transcriptome Analysis Reveals Oncogenic Roles for Rho GTPase-Activating Proteins in Basal-like Breast Cancers. Cancer Res 76:3826-37
Wang, Hui; Vilela, Marco; Winkler, Andreas et al. (2016) LOVTRAP: an optogenetic system for photoinduced protein dissociation. Nat Methods 13:755-8
Hodgson, Louis; Spiering, Désirée; Sabouri-Ghomi, Mohsen et al. (2016) FRET binding antenna reports spatiotemporal dynamics of GDI-Cdc42 GTPase interactions. Nat Chem Biol 12:802-809
MacNevin, Christopher J; Toutchkine, Alexei; Marston, Daniel J et al. (2016) Ratiometric Imaging Using a Single Dye Enables Simultaneous Visualization of Rac1 and Cdc42 Activation. J Am Chem Soc 138:2571-5

Showing the most recent 10 out of 24 publications