IKK FAMILY KINASES REGULATE CELL GROWTH, METABOLISM AND AUTOPHAGY BY PHOSPHORYLATION OF KEY SUBSTRATES

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  • March 20, 2019
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  • Antonia, Ricardo
    • Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology
Abstract
  • Inflammation is now widely accepted to be an essential mediator of the balance between cell growth, metabolism, and autophagy. A group of kinases belonging to the IB kinase (IKK) family has emerged as critical regulators of the interplay between inflammation and energy usage in both healthy and diseased tissues. They accomplish this task by phosphorylation of a variety of protein targets. My dissertation work has focused on two of these phosphorylation targets. In Chapter 2, I characterized the role of IKK in regulating the AMP-activated protein kinase (AMPK), the primary sensor of ATP levels in a cell. I found that IKK directly phosphorylates Thr172 within the AMPK activation loop, both basally in cancer cell lines and in response to cytokine stimulation. Thr172 phosphorylation of AMPK is well-characterized to increase the activity of AMPK and to phosphorylation of downstream AMPK targets. By understanding the mechanism of IKK-mediated AMPK activation, I was able to devise a strategy for exploiting a metabolic weakness of LKB1 deficient lung cancers, which involved combining an IKK inhibitor with the mitochondrial complex I inhibitor phenformin. In Chapter 3, I characterized the mechanism whereby the IKK-related kinase, TANK-binding kinase 1 (TBK1) phosphorylated a critical component of mTORC1, Raptor, which could represent a mechanism whereby TBK1 promotes autophagy. Overall, the work presented here adds to our understanding of the mechanisms of how inflammation can regulate metabolism. Knowledge of these mechanisms will hopefully shed new light on ways to therapeutically restrict the metabolic changes induced by inflammation for therapeutic benefit.
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Advisor
  • Cox, Adrienne
  • Graves, Lee
  • Moorman, Nathaniel
  • Marzluff, William
  • Baldwin, Albert
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2018
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