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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 (IBT), 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 of the Cardiovascular Institute (CVRI), College of Medicine, Texas A&M Health Science Center, member of the Graduate Faculty of Biomedical Sciences (Program in 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, Texas A&M Distinguished Professor in 2008 and is currently Executive Associate Director of IBT. 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, mouse transgenics and proteomics and nanotechnology. Mouse models of human diseases--prostate cancer, hepatoma and liver diseases. 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 the stromal and epithelial compartments as well as vascular and immune system cells 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. In addition to the ubiquitous role of the FGF signaling family in cellular homeostasis, mouse models and human mutations have revealed unsuspected roles of FGF signaling in endocrine metabolic control. These include cholesterol to bile acid, lipid, glucose and calcium phosphate metabolism and associated pathologies. The family has been implicated in the starvation response, obesity, diabetes and diseases associated with metabolic syndrome. This includes non-alcoholic fatty liver disease. These activities work in partnership with co-factors called klothos in addition to heparan sulfate. Surprisingly, we have found that in contrast to the cellular activities of FGF signaling that are involved in tumor promotion, the metabolic roles of FGF signaling are coincident with a role in tumor suppression. Preventing cancer at its mitotic origin through mitotic cell death. Although resident FGF signaling systems in epithelial cells mediates homeostasis-promoting communication with the tissue environment, acquisition of an ectopic member of the family in epithelial cells can be a strong promoter of progression to malignancy. However, the promotion role of FGF signaling alone is insufficient to support full malignancy. It works in cooperation with loss of tumor suppressors that function to kill cells that acquire genetic defects that contribute to the genetic plasticity that is a common property of all cancers. The analysis of cancer genomes is revealing what was suspected over 100 years of observation and treatment. All cancers are different and capable of evading and surviving a wide variety of therapies. A therapy designed for one type of cancer often does not work for another. Diverse cancers exhibit hundreds of genomic differences that cannot be predicted from the normal genome of the patient or from the genome of a precursor to the current cancer. The only common property of all cancers is aneuploidy, too few or too many chromosomes. Aneuploidy happens as a consequence of survival of a random low frequency error in life's most fundamental and essential process, cell division. Frequency can be influenced by environmental factors. Our research group discovered a novel network of dual function microtubule- and mitochondrial-associated proteins that sense an error during cell division that could cause aneuploidy. When an aneuploid division threatens, lethal mitochondria that are normally cleared by a process known as mitophagy unite to kill the defective cells through a process called mitotic cell death even before they can complete the defective cell division and over time give rise to cancer. Enhancement of this mechanism may be a way to prevent initiation of cancers in general at their source and eventually the most effective point of prevention and treatment of cancers in general.
Five Most Significant Publications Prior to 2007Kan, 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. 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]. Publications 2007 Lin 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., Zhang, J., Lin, Y., Lan, Y., Lin, C., Xuan, J.W., Shen, M.M., McKeehan, W.L., Greenberg, N.M., and Wang, F. (2008) Role of epithelial cell fibroblast growth factor receptor substrate 2alpha in prostate development, regeneration and tumorigenesis. Development. 2008 Feb;135(4): 775-784. [Epub 2008 Jan 9] Matsubara, A., Teishima, J., Mirkhat, S., Yasumoto, H., Mochiduki, H., Seki, M., McKeehan, W.L. and Usui, T. (2008) Restoration of FGF receptor type 2 enhances radiosensitivity of hormone-refractory human prostate carcinoma PC-3 cells. Anticancer Res. 2008 Jul-Aug;28(4B):2141-2146. Publications 2009Huang, X., Yang, C., Jin, C., Luo, Y., Wang F. and McKeehan, W.L. (2009) Resident hepatocyte fibroblast growth factor receptor 4 limits hepatocarcinogenesis. Mol. Carcinog. 48: 553-562 [Epub 2008 Nov 13]. Liu, L., Xie, R., Nguyen, S., Ye, M. and McKeehan, W.L. (2009) Robust autophagy/mitophagy persists during mitosis. Cell Cycle 8: 1616-1620 [Epub 2009 May 27]. Luo, Y., Yang, C., Jin, C., Wang, F. and McKeehan, W.L. (2009) Novel phosphotyrosine targets of FGFR2IIIb signaling. Cellular Signal. 21: 1379-1378 [Epub 2009 May 4]. Liu, L., Xie, R., Yang, C. and McKeehan, W.L. (2009) Dual function microtubule- and mitochondria-associated proteins mediate mitotic cell death. Cellular Oncol. 31:393-405. McKeehan, W.L., F. Wang and Y. Luo (2009) The fibroblast growth factor (FGF) signaling complex. Handbook of Cell Signaling 2nd Edition, Vol. I, Chap. 38 (R. Bradshaw and E. Dennis, eds.), Elsevier/MacMillan Press (in press). For complete list of publications, go to PubMed (search: mckeehan wl).
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