Dr. McKeehan | FGF SignalingCell CommunicationMetabolic HomeostasisProstate CancerHepatoma |
Tumor SuppressionStructural BiologyGlycobiology |
Wallace L. McKeehanBiographyWallace L. McKeehan received his undergraduate degree in chemistry at the University of Florida and his Ph.D. in biochemistry at the University of Texas-Austin. He was a research scientist at the Basel Institute for Immunology in Basel, Switzerland and a research associate in the Department of Molecular, Cellular and Developmental Biology at the University of Colorado. Then he joined the W. Alton Jones Cell Science Center in Lake Placid, New York, where he was a senior scientist, deputy director and co-founder of Upstate Biotechnology, Inc. While there he held adjunct faculty appointments in the Department of Biochemistry at the University of Vermont, Department of Chemistry at Clarkson University, and in the Cell Biology Department, Xiamen University, Peoples Republic of China. Dr. McKeehan is currently the J.S. Dunn Professor and Director of the Center for Cancer and Stem Cell Biology at the Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, and Professor in the Department of Biochemistry and Biophysics at Texas A&M University. He is also an associate member of the Intercollegiate Faculty of Nutrition (IFN) and Interdisciplinary Faculty of Reproductive Biology (IFRB) within Texas A&M, member Cardiovascular Institute (CVRI), College of Medicine, Texas A&M, member of the Graduate Faculty of Biomedical Sciences (Program in Cell and Regulatory Biology, Reproductive Biology) at the University of Texas-Houston, and Adjunct Professor in Molecular and Cellular Biology at Baylor College of Medicine. He was named a Texas A&M Regents Professor in 2003. ResearchFailure to communicate underlies cancer and other diseases. Tissues are comprised of a society of diverse cell types that similar to human societies must communicate properly to maintain normal function, peace, tranquility and good health. We believe that the failure to communicate properly underlies most tissue dysfunctions and disease. The laboratory studies how the chemical signals (polypeptide growth factors and cytokines) in the local tissue environment control growth and specialization of different cell types of the prostate, the liver, the vascular system and neural tissue. These signals determine the normal development and function of the tissues while aberrations result in tissue dysfunction and diseases, such as cancer, stroke, atherosclerosis, liver, and neural disease. These signaling systems which are comprised of a signal polypeptide from one cell type and a reception system on another are the basis for communication among cells in tissues, but also serve as sensors of signals like hormones and nutrients that come from outside the tissues. The cellular reception system for many signal polypeptides consists of a transmembrane protein whose external domain interacts with signal polypeptides and an intracellular domain which is a protein kinase enzyme which activates metabolic pathways that control cell growth, function, and gene expression. The Fibroblast Growth Factor (FGF) signaling system is a ubiquitous regulatory system that controls cell to cell communication during embryogenesis and cellular homeostasis within adult tissues. The FGF family is unique in the way that it is intimately interwoven with the peri-cellular matrix through heparan sulfate proteoglycans which are an integral part of the signaling system. The system senses changes in the local environment and transmits them to the interior of cells for a response. The laboratory seeks to understand the molecular mechanisms of assembly of components of the FGF signaling system, its role in homeostasis of prostate, liver and the cardiovascular systems and their dysfunction that results in disease. Technologies employed in the laboratory include recombinant DNA technologies, protein chemistry, expression of recombinant proteins in bacteria, yeast, insect cells and mammalian cells, primary cell culture and tissue reconstitutions, monoclonal antibodies and hybridomas and mouse transgenics. Mouse models of human diseases--prostate cancer, hepatoma and liver diseases. Most recently, a major effort has been in exploitation of mouse genetic technologies to build new mouse models of human prostate and liver diseases by manipulation of both signals and reception in the different cell populations that comprise different compartments in adult parenchymal organs. Only recently has the importance of the communication among diverse cell populations in the microenvironment to health and disease in addition to the primary functional parenchymal cell. In prostate, two-way FGF signaling between stromal cells and epithelial cells that give rise to adenocarcinoma maintains normal health and function of the organ. Breakdown in communication disrupts the balance and frees epithelial cells to become cancer. FGF signaling in cholesterol homeostasis, metabolic syndrome and liver diseases. Mouse models have revealed unsuspected novel roles of FGF signaling in cholesterol to bile acid and fat metabolism in the liver. Only recently has fatty liver (non-alchoholic fatty liver, NAFL) and its consequent effect on fibrosis and hepatoma been recognized as a consequence of the collection of health risks called metabolic syndrome associated with obesity. We are interested in the role of FGF signaling in metabolic syndrome and particularly in NAFL as well as alcoholic fatty liver disease (AFL). This understanding will allow us to design strategies for prevention or treatment of metabolic syndrome-associated diseases and NAFL and AFL targeted at FGF signaling. Cooperation of FGF signaling and suppression of genetic instability--preventing cancer at its mitotic origin. Although resident FGF signaling systems in epithelial cells mediates homeostasis-promoting communication with the tissue environment, acquisition of an ectopic member of the family abnormally activated in epithelial cells appears to be a strong promoter of progression to malignancy. However, promotion alone is often insufficient to support full malignancy and works in cooperation with loss of tumor suppressors that function to kill cells that acquire genetic defects that contribute to the genetic plasticity (aneuploidy) required to maintain a malignant tumor. We have discovered and are studying the role and mechanism of members of a novel network of factors that monitors integrity of the microtubular cytoskeleton and mitochondria during cell division and a potential catastrophe that threatens integrity of the genome. We are studying how the defects at mitosis trigger a unique mode of mitochondrial-associated cell death we describe as mitochondrial-associated genome destruction (MAGD) to prevent inheritance and propagation of a defective genome arising at mitosis. We believe that a defective mitosis and a defect in this detection system that removes the defective cell may be the common origin of all cancers and the most effective point of prevention and treatment of cancer in general. Five Most Significant Publications Prior to 2006Kan, M., F. Wang, J. Xu, E. Shi, J.W. Crabb, J. Hou, and W.L. McKeehan (1993) An essential heparin-binding domain in the fibroblast growth factor receptor kinase. Science 259:1918-1921. Yan, G., Y. Fukabori, G. McBride, S. Nikolaropolous, and W.L. McKeehan (1993) Exon switching and activation of stromal and embryonic fibroblast growth factor (FGF)-FGF receptor genes in prostate epithelial cells accompanies stromal independence and malignancy. Mol. Cell. Biol.13:4513-4522. Feng, S., F. Wang, A. Matsubara, M. Kan and W.L. McKeehan (1997) Fibroblast growth factor receptor 2 limits and receptor 1 accelerates tumorigenicity of prostate epithelial cells. Cancer Res. 57:5369-5378. Yu, C., F. Wang, M. Kan, C. Jin, R.B. Jones, M. Weinstein, C. Deng, and W.L. McKeehan (2000) Elevated cholesterol metabolism and bile acid synthesis in mice lacking membrane tyrosine kinase receptor FGFR4. J. Biol. Chem. 275: 15482-15489. Ye, S., Y. Luo, W. Lu, R.B. Jones, R.J. Linhardt, I. Capila, T. Toida, M. Kan, H. Pelletier and W.L. McKeehan (2001) Structural basis for interaction of FGF-1, FGF-2 and FGF-7 with different heparan sulfate motifs. Biochemistry 40: 14429-14439 Publications 2006 Zhao, P., G. Caretti, S. Mitchell, W.L. McKeehan, A.L. Boskey, L.M. Pachman, V. Sartorelli, and E.P. Hoffman. (2006) Fgfr4 is required for effective muscle regeneration in vivo: Delineation of a MyoD-Tead2-Fgfr4 transcriptional pathway. J. Biol. Chem. 281: 429-438 [Epub 2005 Nov. 2]. Gutierrez, A., E.P. Ratliff, A.M. Andres, X. Huang, W.L. McKeehan and R.A. Davis. (2006) Bile acids decrease hepatic paraoxonase1 expression and plasma HDL levels via FXR-mediated signaling of FGF receptor 4. Arterioscler. Thomb. Vasc. Biol. 26: 301-306 [Epub 2005 Nov. 10]. Luo, Y., S. Ye, M. Kan, and W.L. McKeehan (2006) Structural specificity in a FGF7-affinity purified heparin octasaccharide required for formation of a complex with FGF7 and FGFR2IIIb. J. Cell. Biochem. 97: 1241-1258. [Epub 2005 Nov. 28]. Huang, X., C. Yu, C. Jin, M. Kobayashi, C.A. Bowles, F. Wang, and W.L. McKeehan (2006) Ectopic activity of FGFR1 in hepatocytes accelerates hepatocarcinogenesis by driving proliferation and VEGF-induced angiogenesis. Cancer Res. 66: 1481-1490. Newman, E.A., S.J. Muh, R.H. Hovhannisyan, C.C. Warzecha, R.B. Jones, W.L. McKeehan, and R.P. Carstens (2006) Identification of RNA-binding proteins that regulate FGFR2 splicing through use of sensitive and specific dual color fluorescence minigene assays. RNA 12:1129-1141 [Epub 2006 Apr 7]. Luo, Y., S. Ye, M. Kan and W.L. McKeehan (2006) Control of FGF7- and FGF1-induced mitogenesis and downstream signaling by distinct heparin octasaccharide motifs. J. Biol. Chem. 281:21052-21061 [Epub 2006 May 25]. Huang, X., C. Yu, C. Jin, C. Yang, R. Xie, D. Cao, F. Wang, and W.L. McKeehan (2006) Forced expression of liver fibroblast growth factor 21 delays initiation of chemically-induced hepatocarcinogenesis. Mol. Carcinog. 45: 934-942. (Epub 2006 Aug. 23). Publications 2007Lin Y, G. Liu, Y. Zhang, Y-P. Hu, K. Yu, C. Lin, K. McKeehan, J. W. Xuan, D. Ornitz, M. M. Shen, N. Greenberg, W. L. McKeehan, and F. Wang (2007). Fibroblast growth factor receptor 2 tyrosine kinase is required for prostatic morphogenesis and acquisition of strict androgen dependency for adult tissue homeostasis. Development 134: 723-734 [Epub 2007 Jan 10]. Luo, Y., X. Huang and W.L. McKeehan (2007). High yield, purity and activity of soluble recombinant Bacteriodes thetaiotamicron GST-heparinase I from Escherichia coli. Arch. Biochem. Biophys. 460: 17-24 [Epub 2007 Jan 29]. Moss, T.N., A. Vo, W.L. McKeehan and L. Liu (2007) UXT (Ubiquitously Expressed Transcript) causes mitochondrial aggregation. In Vitro Cell. Devel. Biol. Animal 43: 139-146 [Epub 2007 Mar 21]. Gunasekera R.S., Sewgobind K., Desai S., Dunn L., Black HS., McKeehan W.L., Patil B. (2007) Lycopene and lutein inhibit proliferation in rat prostate carcinoma cells. Nutr Cancer. 58:171-7. Eriksson, M., Samuelsson, H., Samuelsson E-B., Liu, L, McKeehan, W.L., Benedikz, E., Sundstrom, E. (2007) The NMDAR subunit NR3A interacts with microtubule-associated protein 1S in the brain. Biochem. Biophys. Res. Commun. 361: 127-132 [Epub 2007 Jul 16]. Huang, X., Yang, C., Luo, Y., Jin, C., Wang, F. and W.L. McKeehan (2007) FGFR4 prevents hyperlipidemia and insulin resistance but underlies high fat diet-induced fatty liver. Diabetes 56: 2501-10 [Epub 2007 Jul 30]. Publications 2008Zhang, Y., J. Zhang, Y. Lin, Y. Lan, C. Lin, J.W. Xuan, M.M. Shen, W.L. McKeehan, N.M. Greenberg, and F. Wang (2008). Fibroblast growth factor receptor substrate 2alpha-mediated signals in the prostatic epithelium are important for prostate development and tumorigenesis. Development 135:775-784. For complete list of publications, go to PubMed (search: mckeehan wl). |
