Lee A. Witters
Professor of Medicine and Biochemistry and Biological
Sciences
Research Areas: Signal Transduction and Cellular Metabolism
Protein Phosphorylation and Cellular Metabolism
Our laboratory's interest is directed to understanding as to how cells and tissues respond to a number of stresses, such as the availability of oxygen and metabolic substrates like glucose, and as to how the rates of fat and cholesterol synthesis and degradation are regulated. A major area of interest relates to the molecular characterization of a novel protein kinase, that is activated by 5'-AMP. This enzyme, designated AMP-activated protein kinase (AMPK), is activated under conditions of low blood flow (ischemia), low oxygen concentrations (hypoxia) or when glucose is limiting for cellular metabolism. It has a wide tissue distribution and is a unique member of a much larger protein kinase family with homologs in yeast, plants, C. elegans and several mammalian species. The enzyme consists of three subunits, a, b and g; the former is its catalytic subunit and the latter two are non-catalytic regulatory subunits. The metabolite-sensing function of AMPK homologs has been preserved through evolution, indicating the critical nature of its cellular function. Cloning of the genes and cDNAs for AMPK subunits coupled with characterization of their protein products make possible a number of approaches to defining its role in mammalian and other tissues. Current experiments are addressing the functions of all three kinase subunits, the nature of the intracellular substrates for the kinase and the regulation of kinase activity by hormones and other extracellular signals. Being a central regulator of many aspects of metabolism, including fatty acid and cholesterol synthesis, fatty acid oxidation, lipolysis and glucose homeostasis and of cardiac rhythmicity, ion channel function and apoptosis, this work taken together will contribute to expanded knowledge of the pathophysiology and therapy of diabetes mellitus, hyperlipidemia, cardiac function and obesity.
Publications
Iseli TJ, Walter M, van Denderen BJ, Katsis F, Witters LA, Kemp BE, Michell BJ and Stapleton D. (2005) AMPK beta subunit tethers alpha and gamma subunits via its C-terminalsequence, J Biol Chem. 280(14):13395-400
Hurley, RL, Anderson, KA, Franzone, JM, Kemp, BE, Means, AR and Witters, LA (2005), The Ca++/calmodulin-dependent protein kinase kinases are AMP-activated protein kinase kinases, J Biol Chem, 280. 29060-29066 ( Papers In Press, June 24, 2005)
Witters, LA, Kemp, BE, and Means, AR (2006), Chutes and ladders; the search for protein kinases active on AMPK, TiBS, 31, 13-15. 3329-3335.