Larry Fliegel
Larry Fliegel (PhD, University of Calgary)
Professor and Associate Chair
Department of Biochemistry
Faculty of Medicine & Dentistry
University of Alberta
347 Medical Sciences Building
Edmonton, Alberta, Canada T6G 2H7
Tel: 780.492.1848
Lab Tel: 780.492.1847
Fax: 780.492.0886
lfliegel@ualberta.ca
Lab Website
Research Description
Handling acid is a problem in all organisms. As a result of metabolism, excess intracellular acid is produced in all cells. Too much acid has a deleterious effect on the activity of various enzymes and results in abnormalities in metabolism and cell cycle. In the heart, too much acid inhibits contractile activity and damages the myocardium. Our laboratory studies the regulation of intracellular pH and the removal of excess intracellular acid. In mammalian tissues the main protein responsible for this is the Na+/H+ exchanger. The Na+/H+exchanger is a mammalian plasma membrane protein that exchanges one intracellular proton for an extracellular sodium. It is involved in pH regulation and is stimulated by growth factors. Several isoforms of the protein exist (NHE1 to NHE10). NHE1 is the most widespread and exists in all mammalian cells. My laboratory has studied many aspects of the NHE1 protein. We have examined the structure and characterized activity of the protein. We have used site-specific mutagenesis to discover which amino acids are important in transport and have examined the structure of parts of the cytosolic and membrane domains. In collaboration with others we have elucidated the structure of parts of the membrane domain of the protein. My laboratory has also studied phosphorylation of the antiporter and factors affecting localization and targeting of the protein. We have a special interest in the Na+/H+ exchanger in the mammalian heart, because the protein is important in heart disease. In the heart we have examined regulation of expression and activity of the protein. We have shown that MAP kinase dependent pathways are key to the regulation of activity of the Na+/H+ exchanger. Both p90rsk and MAP kinase are key protein kinases involved in regulation of activity of the protein. We also have a great interest in pH regulation and ion movements in yeast. In Schizosaccharomyces pombe the Na+/H+ exchanger (sod2) moves Na+ out of the cell in exchange for H+. This protein functions in osmotolerance in yeast and plants. We have examined amino acids important in cation binding and transport in this protein. Overall, our long-term goal is to understand how ions and coordinated and transported in membrane proteins. The laboratory continues to be involved in new and exciting studies on regulation of activity and expression of Na+/H+ exchange proteins. Many new projects are underway. We are always interested in recruiting high quality personnel so please contact me if you are interested in this area.
Selected publications
Amith, S. R., and Fliegel, L. (2016) The Na+/H+ exchanger in metastasis. Aging (Albany NY) 8, 1291. 27434610. 10.18632/aging.101002
Amith, S. R., Fong, S., Baksh, S., and Fliegel, L. (2015) Na (+)/H (+) exchange in the tumour microenvironment: does NHE1 drive breast cancer carcinogenesis? Int J Dev Biol 59, 367-377. 26679950. 10.1387/ijdb.140336lf
Amith, S. R., Wilkinson, J. M., and Fliegel, L. (2016) Na+/H+ exchanger NHE1 regulation modulates metastatic potential and epithelial-mesenchymal transition of triple-negative breast cancer cells. Oncotarget 7, 21091-21113. 27049728. 10.18632/oncotarget.8520
Ullah, A., Dutta, D., and Fliegel, L. (2016) Expression and characterization of the SOS1 Arabidopsis salt tolerance protein. Mol Cell Biochem 415, 133-143. 26992907. 10.1007/s11010-016-2685-2
Amith SR, Wilkinson JM and Fliegel L. Characterization of the role of phosphorylation sites in regulation of the Na+/H+ exchanger (NHE1) in triple-negative MDA-MB-231 breast cancer cells. In Press in Oncotarget.Claire Guissart, Xiuju Li, Bruno Leheup, Nathalie Drouot, Philippe Jonveaux, Larry Fliegel, Michel Koenig. (2015) Mutation of SLC9A1, encoding the major Na+/H+ exchanger, causes ataxia-deafness Lichtenstein Knorr syndrome. Human Molecular Genetics 24(2):463-70. DOI 10.1093/hmg/ddu461.
Schammim Ray Amith, Jodi Marie Wilkinson, S. Baksh and Larry Fliegel (2015) The Na+/H+ exchanger (NHE1) as a novel co-adjuvant target in paclitaxel therapy of triple-negative breast cancer cells. Oncotarget 6(2):1262-75. Accession # 25514463 ISSN 1949-2553
Li, X. and Fliegel, L. (2015) A Novel Human Mutation in the SLC9A1 Gene Results in Abolition of Na+/H+ Exchanger Activity. Plos One 10(3) e0119453
Iman A. Mohamed, Alain-Pierre Gadeau, Gary Lopaschuk, Larry Fliegel, Mohamed Mlih, Nabeel Abdulrahman, Natasha Fillmore, Fatima Mraiche. Na+/H+ Exchanger Isoform 1-Induced Osteopontin Expression Facilitates Cardiomyocyte Hypertrophy Through p90 Ribosomal S6 Kinase. (2015) PLOS One 10(4) e0123318.
Amith, R.S, S. Fong, S. Baksh and L. Fliegel. Na+/H+ Exchange in the Tumour Microenvironment: Does NHE1 Drive Breast Cancer Carcinogenesis? International Journal of Developmental Biology. In Press March 23, 2015.
S.C. Guffey, L. Fliegel, G.G. Goss. (2015) Cloning and characterization of shark gill Na+/H+ Exchanger isoforms NHE2 and NHE3 from the Pacific dogfish Squalus suckleyi In Press in Comparative Biochemistry and Physiology - Part B: Biochemistry & Molecular Biology
Y. Liu, A. Basu, Xiuju Li and L. Fliegel. Topological Analysis of the Na+/H+ Exchanger. In Press BBA Biomembranes (July 22/2015)
Kemp, G., Fliegel, L., and Young, H.S. (2014) Membrane transport piece by piece: production of transmembrane peptides for structural and functional studies. Curr. Protoc. Protein Sci. 75:Unit 29 28.
Ullah, A., El-Magd, R.A., and Fliegel, L. (2014) Functional role and analysis of cysteine residues of the salt tolerance protein Sod2. Mol. Cell Biochem. 386:85-98.
Li, X., Prins, D., Michalak, M., and Fliegel, L. (2013) Calmodulin-dependent binding to the NHE1 cytosolic tail mediates activation of the Na+/H+ exchanger by Ca2+ and endothelin. Am. J. Physiol. Cell Physiol. 305:C1161-1169.
Ullah, A., Kemp, G., Lee, B.L., Alves, C., Young, H., Sykes, B.D. and Fliegel, L. (2013) Structural and functional analysis of transmembrane segment IV of the salt tolerance protein Sod2. J. Biol.Chem. 288:24609-24624.
Odunewu, A. and Fliegel, L. (2013) Acidosis-mediated regulation of the NHE1 isoform of the Na(+)/H(+) exchanger in renal cells. Am. J. Physiol. Renal Physiol. 305:F370-381.
Li, X., Khan, M.F., Schriemer, D.C., and Fliegel, L. (2013) Structural changes in the C-terminal regulatory region of the Na(+)/H(+) exchanger mediate phosphorylation induced regulation. J. Mol. Cell Cardiol. 61:153-163.
Amith, S.R. and Fliegel, L. (2013) Regulation of the Na+/H+ Exchanger (NHE1) in Breast Cancer Metastasis. Cancer Res. 73:1259-1264.
Lee, B.L., Sykes, B.D., and Fliegel, L. (2013) Structural and functional insights into the cardiac Na(+)/H(+) exchanger. J. Mol. Cell Cardiol. 61:60-67.
http://www2.biochem.ualberta.