Liberal Arts and Sciences Science Endowed Chair, UIC Distinguished Professor, and Head
4508 SES, MC 111
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Chemical biology of cell signaling and regulation: Optical Imaging of cellular processes and development of molecular sensors: Small molecule modulation of cell signaling: New regulatory roles of membrane lipids and lipid binding proteins
Cellular processes, such as cell signaling, are mediated by myriad of protein-protein interactions that are exquisitely coordinated and tightly regulated. Our recent studies have shown that membrane lipids play key roles in this complex regulation. Our current research focuses on i) understanding how lipids perform their regulatory actions, ii) discovering their new cellular functions, iii) and developing new therapeutics and novel strategies to treat diverse human diseases caused by dysfunctional lipid-regulated processes, including cancer, autoimmune diseases, inflammatory diseases, and metabolic diseases.
(1) Seeing is believing and it is numbers that matter
Lipids are ubiquitous and dynamic regulatory molecules and their biological functions depend on their subcellular locations and local concentrations. Our newly developed in situ quantitative lipid imaging technology (Nature Chemistry, 2011) has not only demonstrated high-resolution spatiotemporal dynamics of various lipids but also provided new insight into how lipid molecules regulate complex cellular processes. We are currently developing specific fluorescence-based sensors for a wide variety of lipids. These sensors will help us elucidate the cellular dynamics of these lipids and discover their new cellular activities. They can be also used as biomarkers for various human diseases. We are also developing new imaging technologies to simultaneously monitor cellular concentrations of multiple lipids and the activities of lipid-binding proteins in live cells and tissues.
Our in situ quantitative imaging demonstrates how the concentration of a lipid fluctuates during phagocytosis of a macrophage. Dramatic enrichment of the lipid (red spikes) is shown in the pseudopod of the macrophage that wraps around a target cell
(2) Multi-talented cholesterol: New regulatory roles of cholesterol and other lipids
Cholesterol is a major lipid component of the mammalian plasma membrane. While much is known about the metabolism and transport of cholesterol and its role in cardiovascular diseases, less is known about the exact cellular function of cholesterol. We recently discovered that cholesterol directly activates diverse cell signaling pathways, including canonical Wnt signaling that leads to cell growth and proliferation (Nature Communications, 2012, 2014). More recent studies have revealed that cholesterol can specifically regulate other cellular processes. Using our new cholesterol sensors, we also found that unique membrane distribution of cholesterol is crucial for its cellular regulatory function. On the basis of these exciting new discoveries, we are currently investigating the regulatory roles of cholesterol in a wide range of biological processes and developing new chemical and biological strategies to modulate cholesterol-mediated processes. The same approach is also being applied to the study of other lipids.
(3) Lipids as master regulators of cellular processes
Cellular processes are mediated by a complex array of protein-protein interactions. Our recent studies have shown that membrane lipids spatiotemporally regulate cellular protein-protein interactions by directly binding and modulating the function of modular domains that mediate protein-protein interactions (Molecular Cell, 2012). Through extensive collaboration with structural, computational, and biological laboratories, our current work focuses on identifying and characterizing new classes of lipid binding proteins on a genomic scale and elucidating how lipids control diverse biological processes mediated by these proteins. We are also developing new chemical and imaging tools that allow specific manipulation and quantitative monitoring of their actions in live cells and tissues.
(4) New lipid drugs for human diseases: Small molecule modulators of cellular lipid-protein and protein-protein interactions
Allosteric drugs are an emerging class of compounds that target allosteric sites of proteins. Since many lipids serve as allosteric regulators for cellular proteins, small molecules modulating lipid-protein interaction might act as novel and potent allosteric inhibitors. Using our newly developed high-throughput lipid-protein binding assay, we are searching for small molecules that can specifically modulate lipid binding of various pharmacologically important cellular proteins. These molecules will be optimized and tested for in vivo activities.
- Yoon, Y., Lee, P.J., Kurilova, S., and Cho, W. (2011), In Situ Quantitative Imaging of Cellular Lipids Using Molecular Sensors. Nature Chemistry 3, 868-74. [Featured in ASBMB Today, RSC Chemistry World, ScienceDaily and UIC News]
- Chen, Y., Sheng, R., Kallberg, M., Silkov, A., Tun, M.P., Bhardwaj, N., Kurilova, S., Hall, R.A., Honig, B., Lu, H., and Cho, W. (2012) Genome-Wide Functional Annotation of Dual Specificity Protein- and Lipid-Binding Modules That Regulate Protein Interactions. Molecular Cell 46, 226-237. [Featured in Faculty of 1000, ScienceDaily and UIC News]
- Sheng, R., Chen, Y., Gee, H. Y., Stec, E., Melowic, H.R., Blatner, N.R., Tun, M.P, Kim, Y., Kallberg, M., Fujiwara, T., Hong, J.H., Kim, K.P., Lu, H., Kusumi, A., Lee, M.G. and Cho W. (2012) Cholesterol Modulates Cell Signaling and Protein Networking by Specifically Interacting with PDZ Domain-Containing Scaffolding Proteins. Nature Communications 3, 1249 DOI: 10.1038/ncomms2221. [Featured in National Institute of General Medical Sciences News and UIC News]
- Sheng, R., Kim, H., Lee, H., Xin, Y., Chen, Y., Tian, W., Choi, J.-C., Doh, J., Han, J.-K. and Cho, W. (2014), Cholesterol Selectively Activates Canonical Wnt Signaling over Non-Canonical Wnt Signaling. Nature Communications 5:4393 doi: 10.1038/ncomms5393
- Liu, S.-L., Sheng, R., O’Connor, M.J., Cui, Y., Yoon, Y. Kurilova, S., Lee, D., and Cho, W. (2014) Simultaneous In Situ Quantification of Two Cellular Lipid Pools Using Orthogonal Fluorescent Sensors. Angew. Chem. Int. Ed. 53, 14387-14391
- Kim, D.H., Park, M.-J., Gwon, G.H., Silkov, A., B. Xu, Z.-Y, Yang, E.C., Song, K., Song, K., Kim, Y., Yoon, H.S., Honig, B., Cho, W.*, Cho, Y.*, and Hwang, I.* (2014) An Ankyrin Repeat Domain of AKR2 Drives Chloroplast Targeting through Coincident Binding of Two Chloroplast Lipids Developmental Cell 30, 598-609 (*corresponding authors) <Featured in Preview>
- Agarwal, S., Kim, H., Chen, R.B., Agarwal, S., Williamson, R., Cho, W., Di Paolo, G., and Satchell, K. J. F. (2015) Autophagy and endosomal trafficking inhibition by Vibrio cholerae MARTX toxin phosphatidylinositol-3-phosphate specific phospholipase A1 activity Nature Communications 6:8745. doi: 10.1038/ncomms9745.
- Park, M-J, Sheng, R., Silkov, A., Jung, D-J, Wang, Z-G, Xin, Y., Kim, H., Thiagarajan-Rosenkranz, P., Song, S., Yoon, Y., Nam, W., Kim, I., Kim, E., Lee, D-G, Chen, Y., Singaram, I., Wang. L. Jang, M.H., Hwang, C.-S., Honig, B., Ryu, S.H., Lorieau, J., Kim, Y-M, and Cho, W. (2016) SH2 domains serve as lipid binding modules for pTyr-signaling proteins. Molecular Cell 62, 7-20. [Highlighted in Nature Reviews in Molecular Cell Biology and Cancer Discovery]
- Francis, K.R., Ton, A.N., Xin, Y., O’Halloran, P.E., Wassif, C.A., Malik, N., Williams, I.M., Cluzeau, C.V., Trivedi, N.S., Pavan, W.J., Cho, W., Westphal, H., Porter, F.D. (2016) Modeling the cholesterol synthesis disorder Smith-Lemli-Opitz Syndrome with iPS cells reveals Wnt/b-catenin defects are causative for neural phenotype. Nature Medicine 22, 388-396 [Featured in News & Views]
- Komura, N., Suzuki, K. G. N., Ando, H., Konishi, M., Koikeda, M., Imamura, A., Chadda, R., Fujiwara, T.K., Tsuboi, H., Sheng, R., Cho, W., Ishida, H., Kusumi, A., Kiso, M. (2016) Raft-based interactions of gangliosides with a GPI-anchored receptor. Nature Chemical Biology 12, 402-410
- Liu, S.-L., Sheng, R., Jung, J.H., Wang, L., Stec, E., O’Connor, M.J. Song, S., Bikkavilli, R.K., Baek, K., Winn, R.A., Lee, D., Ueda, K., Levitan, I., Kim, K.-P., and Cho, W. (2017) Orthogonal lipid sensors identify transbilayer asymmetry of plasma membrane cholesterol Nature Chemical Biology, 13, 268-274
- Liu, S.-L., Wang, Z., Hu, Y., Xin, Y., Gorai, S., Sharma, A., Zhou, X., Gong, L-W., Hay, N., Zhang, J. and Cho, W. Quantitative lipid imaging reveals a new signaling function of phosphatidylinositol-3,4-bisphosphate: Isoform and subcellular site-specific activation of Akt (2018) Molecular Cell 71, 1092-1104
- Zhang, Y., Bulkley, D.P., Xin, Y., Roberts, K.J., Asarnow, D.E., Sharma, A., Myers, B.R., Cho, W.*, Cheng, Y.*, Beachy*, P.A. Structural basis for cholesterol transport-like activity of the Hedgehog receptor Patched (2018) Cell 175, 1352-1364 (*Co-corresponding authors)
- Arthritis Investigator, 1992
- Established Investigator, American Heart Association, 1999
- Graduate Mentoring Award, University of Illinois at Chicago, 2009
- Researcher of the Year Award, University of Illinois at Chicago, 2015
- Avanti Award, Biophysical Society, 2018
- Elected Fellow, American Association for the Advancement of Science, 2018
Service to Community
- Editorial Board, Journal of Biological Chemistry, 2001-2006
- Editorial Board, Progress in Lipid Research, 2010-present
- BS, Seoul National University, 1980; MS, Seoul National University, 1982
- PhD, University of Chicago, 1988
- Postdoctoral Fellow, California Institute of Technology, 1988-1990