10/21/2024
By Sharon Shechter
Degree: Doctoral
Program: Chemistry
Date: Monday, October 28, 2024
From: 2 - 4 a.m.
Location: Olney Hall, Room 518
Thesis/Dissertation Title: Kinases: Have We Truly Explored It All?
Committee Chair:
Matthew Gage, Ph.D., Department of Chemistry, University of Massachusetts Lowell
Committee Members:
Valeri Barsegov, Ph.D., Department of Chemistry, University of Massachusetts Lowell
Hwai-Chen Guo, Ph.D., Department of Chemistry, University of Massachusetts Lowell
Jin Xu, Ph.D., Department of Chemistry, University of Massachusetts Lowell
Brief Abstract:
Kinases serve as regulatory signaling proteins and are crucial for various biological and cellular functions, including cell growth, division, metabolism, signaling, and response to environmental stimuli. They facilitate the transfer of phosphate groups from ATP to specific target molecules—such as proteins, lipids, and carbohydrates—in a process known as phosphorylation. This modification can activate or deactivate target molecules, thereby modulating their function and enabling their participation in cellular signaling pathways. In this dissertation, two protein kinases were highlighted. RIOK1 emerged as a novel potential target in high microsatellite instability (MSI-High) p53 mutant colorectal cancer cells. An integrated analysis using proteomics, bioinformatics, cell genotype, and in vitro experiments determined its effects in colorectal cancer (CRC) MSI-High cell lines depend on p53 and KRAS genotypes. The second kinase investigated was p70S6K, a previously identified anti-cancer target, which we demonstrate as a potential anti-COVID-19 target. A multidisciplinary approach, including in vitro experiments and in silico bioinformatics and cheminformatics analyses, revealed that p70S6K, which operates downstream of the PI3K/mTOR signaling pathway that is often exploited by viruses, could serve as a target for treating COVID-19 infection. These findings highlight the synergy of integrating proteomics, specifically phosphorylation data, with in-silico and wet-bench experiments to reveal non-obvious mechanistic insights into kinases that might otherwise elude expert-level analysis.