Characterization of T2R14 signaling mechanisms in extraoral tissues

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dc.contributor.authorShaik, Feroz Ahmed
dc.contributor.examiningcommitteeBhullar, Rajinder Pal (Oral Biology) Duan, Kangmin (Oral Biology) Arthur, Gilbert (Biochemistry and Medical Genetics) Hwa, John (Cardiovascular Medicine, Yale University)en_US
dc.contributor.supervisorChelikani, Prashen (Oral Biology)en_US
dc.date.accessioned2019-07-12T18:53:21Z
dc.date.available2019-07-12T18:53:21Z
dc.date.issued2019-07-09en_US
dc.date.submitted2019-07-09T05:26:13Zen
dc.degree.disciplineOral Biologyen_US
dc.degree.levelDoctor of Philosophy (Ph.D.)en_US
dc.description.abstractBitter taste receptors (referred to as T2Rs) are integral cell membrane receptors that belong to G protein-coupled receptor family. In humans, 25 T2R subtypes have been discovered thus far, and are differentially expressed in various organs. Embracing the newly recognized extraoral and functional roles of T2Rs, I investigated the significance of select T2Rs in pathophysiological conditions. The function of T2Rs in breast cancer is not clearly understood. We characterized the expression and function of T2R4 and T2R14 in breast cancer clinical samples and analyzed their physiological role using highly metastatic breast cancer and non-cancerous cell lines. The results show that compared to normal breast epithelial cells, intrinsic activation of T2Rs in breast cancer cells elicited anti-proliferative, anti-migratory and pro-apoptotic responses. These findings demonstrate that the chemosensory T2R signaling network is involved in evoking beneficial physiological responses in breast cancer. The second part of my thesis involved identifying intrinsic factors regulating T2R14 signaling in airways. The pathophysiological relevance of T2R14 in airway cells is well recognized. Using human airway smooth muscle cells and human bronchial epithelial cells, I studied the role of membrane lipids, cholesterol and sphingomyelin, in airway T2R14 signaling. The results reveal that membrane cholesterol regulates T2R14 signaling, however, T2R14 signaling was not dependent on the availability of sphingomyelin. Furthermore, this work identified the site on T2R14 that potentially binds cholesterol. The final part of my thesis involved identification of a highly conserved histidine (H208) on the intracellular side of T2R14 in determining agonist selectivity. Structure-function analysis of H208 suggests its role in regulating T2R14 active conformation and consequentially agonist promoted downstream signaling. Collectively, these studies provide novel insights into various factors governing the T2R14 signaling in extraoral tissues.en_US
dc.description.noteOctober 2019en_US
dc.identifier.citationShaik, F. A., Singh, N., Arakawa, M., Duan, K., Bhullar, R. P., & Chelikani, P. (2016). Bitter taste receptors: Extraoral roles in pathophysiology. Int J Biochem Cell Biol, 77(Pt B), 197-204. doi:10.1016/j.biocel.2016.03.011en_US
dc.identifier.citationShaik, F. A., Medapati, M. R., & Chelikani, P. (2018). Cholesterol modulates signaling of the chemosensory bitter taste receptor T2R14 in human airway cells. Am J Physiol Lung Cell Mol Physiol. doi:10.1152/ajplung.00169.2018en_US
dc.identifier.urihttp://hdl.handle.net/1993/34031
dc.language.isoengen_US
dc.rightsopen accessen_US
dc.subjectGPCRen_US
dc.subjectBitter taste receptorsen_US
dc.subjectT2R14en_US
dc.titleCharacterization of T2R14 signaling mechanisms in extraoral tissuesen_US
dc.typedoctoral thesisen_US
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