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.
|Cook, Aaron A; Deng, Wei; Ren, Jinqi et al. (2018) Calcium-induced structural rearrangements release autoinhibition in the Rap-GEF CalDAG-GEFI. J Biol Chem 293:8521-8529|
|Segal, Dagan; Zaritsky, Assaf; Schejter, Eyal D et al. (2018) Feedback inhibition of actin on Rho mediates content release from large secretory vesicles. J Cell Biol 217:1815-1826|
|Graham, David M; Andersen, Tomas; Sharek, Lisa et al. (2018) Enucleated cells reveal differential roles of the nucleus in cell migration, polarity, and mechanotransduction. J Cell Biol 217:895-914|
|Ma, Xiao; Dagliyan, Onur; Hahn, Klaus M et al. (2018) Profiling cellular morphodynamics by spatiotemporal spectrum decomposition. PLoS Comput Biol 14:e1006321|
|Zaritsky, Assaf (2018) Sharing and reusing cell image data. Mol Biol Cell 29:1274-1280|
|Tajadura-Ortega, Virginia; Garg, Ritu; Allen, Richard et al. (2018) An RNAi screen of Rho signalling networks identifies RhoH as a regulator of Rac1 in prostate cancer cell migration. BMC Biol 16:29|
|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|
|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|
|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:|
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