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Nirav Shah dissertation 08-09-2018 .pdf (3.09 MB)

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Novel signaling mechanisms for Transforming Growth Factor-beta; activated kinase-1 (TAK1) in microtubule and endoplasmic reticulum dynamics

Shah, Nirav, Shah
http://rave.ohiolink.edu/etdc/view?acc_num=osu1533504058135598

Abstract Details

2018, Doctor of Philosophy, Ohio State University, Pharmacology.
The transforming growth factor-beta (TGF-beta) signaling pathway plays a ubiquitous role in developmental and cellular processes by regulating transcription, translation and post-translational modifications to biomolecules. With an army of ligands, receptors, and intracellular mediators, TGF-beta signaling performs functions which are cell-context specific, adapting to the needs of a given organ system. The malfunction of one or more components in the TGF-beta signaling pathway can lead to pathophysiological consequences like cancer, inflammation, cardiovascular disorders, neuro-degenerative diseases and others. Transforming growth factor-beta associated kinase-1 (TAK1) is a serine-threonine kinase that belongs to the non-canonical arm of the TGF-beta signaling family and modulates functions of TAK1 substrates by phosphorylation or ubiquitination. Recently, there has been substantial interest in determining whether TAK1 might serve as a potential therapeutic target due to its invaluable role in relaying inflammatory signals. However, more research needs to be done to understand the role of TAK1 in response to TGF-beta signaling. In this dissertation we explore the role that TAK1 plays in cellular and animal models in the context of TGF-beta signaling. First, we identify a novel TAK1 phospho-substrate, alpha-N-acetyltransferase enzyme (aTAT1) and define the mechanism by which TAK1 enhances aTAT1 activity, thereby leading to hyperacetylation of microtubules. This novel signaling cascade regulates protein trafficking and cell proliferation in both normal and cancerous cells as well as in mice. We predict that further investigation of this signaling cascade in cancer and neuro-degenerative disease models could shed light on better therapeutic strategies. Second, we show that, in addition to regulating microtubule dynamics, TAK1 also engenders morphological changes in the endoplasmic reticulum (ER) that favor the formation of ER tubules. Such rapid transitions in ER morphology affect calcium signaling in cells. Studies are on-going to define the mechanisms by which TAK1-mediated changes in ER morphology regulate cellular outcomes associated with calcium signaling. Thus, this dissertation offers insight into the ability of TGF-beta signaling to execute rapid post-translational modifications to cellular proteins and thereby regulate processes like protein trafficking, cell proliferation, and calcium signaling. This research will help further our ability to identify therapeutic targets germane to cancer immunotherapy and neuro-degenerative diseases.
Dale Hoyt (Committee Chair)
149 p.
Biochemistry; Cellular Biology; Pharmacology

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Citations

  • Shah, Shah, N. (2018). Novel signaling mechanisms for Transforming Growth Factor-beta; activated kinase-1 (TAK1) in microtubule and endoplasmic reticulum dynamics [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1533504058135598

    APA Style (7th edition)

  • Shah, Shah, Nirav. Novel signaling mechanisms for Transforming Growth Factor-beta; activated kinase-1 (TAK1) in microtubule and endoplasmic reticulum dynamics . 2018. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1533504058135598.

    MLA Style (8th edition)

  • Shah, Shah, Nirav. "Novel signaling mechanisms for Transforming Growth Factor-beta; activated kinase-1 (TAK1) in microtubule and endoplasmic reticulum dynamics ." Doctoral dissertation, Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1533504058135598

    Chicago Manual of Style (17th edition)

osu1533504058135598
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