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Wallace L. McKeehan

Wallace L. McKeehan

Professor, J.S. Dunn Foundation Endowed Chair, Texas A&M Regents and Distinguished Professor

Center for Cancer & Stem Cell Biology
2121 W. Holcombe Blvd
Houston, TX   77030-3303

Phone: 713-677-7522
wmckeehan@ibt.tamhsc.edu

Education and Training

Since 1993 Dr. McKeehan has been the endowed J.S. Dunn Professor at the Institute of Biosciences and Technology (IBT) on the Texas A&M Health Science Center Houston Campus with a joint appointment in the Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M Health Science Center.  He is 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 at the University of Texas-Houston, and Adjunct Professor in Molecular and Cellular Biology at Baylor College of Medicine.  He founded and served as Director of the Center for Cancer Biology and Nutrition and later the Center for Cancer and Stem Cell Biology until 2012.

He was named a Texas A&M Regents Professor in 2003, Texas A&M Distinguished Professor in 2008 and served as Associate Director of IBT 1994-2001 and 2009-2012.  Chemistry Family History | Texas Family History

Research Interests

Failure 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.  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. 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 results in autonomy of epithelial cells observed in cancer. The laboratory was the first to show in the early 90's using prostate cancer as a model that FGF signaling was receptor isotype-specific depending on cell context and cell-specific co-factors.

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, in contrast to the cellular activities of FGF signaling that are involved in tumor promotion, the metabolic roles of FGF signaling are not directly mitogenic and coincident with a role in tumor suppression.  The laboratory was first to implicate FGF signaling in control of metabolic homeostasis in 2000 opening up the subfield of endocrine activities of circulating endocrine FGFs as opposed to their canonical roles in local cell to cell communication.    

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.  Based on the discovery in 1993 of the novel protein, LRPPRC, our research group described 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.

Publications

Five Most Significant Publications Prior to 2012

McKeehan WL (1982) Glycolysis, glutaminolysis and cell proliferation.  Cell Biol Int Rep. 1982 Jul;6(7):635-50. PMID: 6751566

Kan, 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.

Hou J, Wang F, McKeehan WL (1994) Molecular cloning and expression of the gene for a major leucine-rich protein from human hepatoblastoma cells (HepG2). In Vitro Cell Dev Biol Anim. 1994 Feb;30A(2):111-4.  PMID: 8012652

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.

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.

Publications 2012

Wang, F., McKeehan, W.L., Shen, M.M., and Abate-Shen, C. (2012) Genetically Engineered Mouse Models in Prostate Cancer Research. In: D. J. Tindall & P.T. Scardino, eds. Recent Advances in Prostate Cancer: Basic Science Discoveries and Clinical Advances, pp 219-282, World Scientific eBooks

Zhang J, Liu J, Huang Y, Chang J, Liu L, McKeehan WL, Martin JF, Wang F. FRS2a-mediated FGF signals suppress premature differentiation of cardiac stem cells through regulating autophagy activity Circulation Research 2012, 110(4):e29-39. PMID: 22207710.

Zhang J, Liu J, Liu L, McKeehan WL, Wang F. The fibroblast growth factor signaling axis controls cardiac stem cells differentiation through autophagy regulation. Autophagy 2012, 8(4). PMID: 22302007

Liu L, McKeehan WL, Wang F, Xie R. MAP1S enhances autophagy to suppress tumorigenesis. (2012) Autophagy 8(2): 278-280. PMID: 22301994.

Yang X, Li Q, Lin X, Ma Y, Yue X, Tao Z, Wang F, McKeehan WL, Wei L, Schwartz RJ, Chang J. (2012) Mechanism of fibrotic cardiomyopathy in mice expressing truncated Rho-associated coiled-coil protein kinase 1. FASEB J. 26(5):2105-16 [EPub 2012 Jan 25] PMID: 22278938

Zhang J, Liu J, Liu L, McKeehan WL, Wang F. The fibroblast growth factor signaling axis controls cardiac stem cell differentiation through regulating autophagy. Autophagy 8(4) [Epub 2012 Apr 1] PMID: 22302007

Yang C, Jin C, Wang F, McKeehan WL, Luo Y. (2012) Differential specificity of endocrine FGF19 and FGF21 to FGFR1 and FGFR4 in complex with KLB.  PLoS ONE 7(3):e33870 [EPub 2012 Mar 19] PMID: 22442730

Lu W, Hu Y, Chen G, Chen Z, Zhang H, Wang F, Feng L, Pelicano H, Wang H, Keating MJ, Liu J, McKeehan W, Wang H, Luo Y, Huang P. (2012) Novel role of NOX in supporting aerobic gycolysis in cancer cells with mitochondrial dysfunction and as a potential target for cancer therapy.  PLoS Biol. 10(5):e1001326. [Epub 2012 May 8] PMID: 22589701

McKeehan WL.  A tribute to Richard G. Ham (1932-2011).  (2012) In Vitro Cell Dev Biol Anim. 48(5): 259-270 [Epub 2012 May 12] PMID: 22580908

Dong W, Lu W, McKeehan WL, Luo Y, Ye S (2012) Structural basic of heparan sulfate-specific degradation by heparinase III. Protein Cell 3(12):950-61 [Epub 2012 July 21]

Emmenegger BA, Hwang EI, Moore C, Markant SL, Brun SN, Dutton JW, Read TA, Fogarty MP, Singh AR, Durden DL, Yang C, McKeehan WL, Wechsler-Reya RJ (2012) Distinct roles for fibroblast growth factor signaling in cerebellar development and medulloblastoma. (2013) Oncogene 32(35):4181-8. doi: 10.1038/onc.2012.440. [Epub 2012 Oct 8] PMID: 23045271

Yang C, Wang C, Ye M, Jin C, He W, Wang F, McKeehan WL, Luo Y.  (2012) Control of lipid metabolism by adipocyte FGFR1-mediated adipohepatic communication during hepatic stress.  Nutr Metab (Lond). 9(1):94 [Epub 2012 Oct 30]
 
Foltz IN, Hu S, King C, Wu X, Yang C, Wang W, Weiszmann J, Stevens J, Chen JS, Nuanmanee N, Gupte J, Komorowski R, Sekirov L, Hager T, Arora T, Ge H, Baribault H, Wang F, Sheng J, Karow JM, Wang M, Luo Y, McKeehan W, Wang Z, Véniant MM, Li Y. (2012) Treating diabetes and obesity with an FGF21-mimetic antibody activating the ßKlotho/FGFR1c receptor complex.  Sci Transl Med 4(162):162ra153

Publications 2013

Yang C, Lu W, Lin T, You P, Ye M, Huang Y, Jiang X, Wang C, Wang F, Lee MH, Yeung SC, Johnson RL, Wei C, Tsai RY, Frazier ML, McKeehan WL, Luo Y. (2013) Activation of liver FGF21 in hepatocarcinogenesis and during hepatic stress.  BMC Gastroenterol.13(1):67. [Epub 17 Apr 2013]

Wang C, Chang JYF, Yang C, Huang Y, Liu J, You P,  McKeehan WL, Wang F, Li X (2013) Type 1 fibroblast growth factor receptor in cranial neural crest cells-derived mesenchyme is required for palatogenesis. J Biol Chem. 2013 Jul 26;288(30):22174-83. doi: 10.1074/jbc.M113.463620 [Epub 2013 Jun 10]  PMID: 23754280

Chang JYF, Wang C, Jin C, Yang C, Huang Y, Liu J, McKeehan WL, D’Souza RN,  Wang F (2013) Self-renewal and multilineage differentiation of mouse dental epithelial stem cells. Stem Cell Res. 2013 Jul 1;11(3):990-1002. doi: 10.1016/j.scr.2013.06.008. [Epub ahead of print] PMID: 23906788

Chang, JYF, Wang C, Jin C, Yang C, Huang Y, Liu J, D’Souza RN, McKeehan WL, Wang F (2013) Fibroblast growth factor signaling is essential for self-renewal of tooth epithelial stem cells. J Biol Chem. 4;288(40):28952-28961 [Epub 2013 Aug 26] PMID: 23979135

Corn P, Wang F, McKeehan WL, Navone N. (2013) Targeting fibroblast growth factor pathways in prostate cancer. Clin Cancer Res. 2013 Nov 1;19(21):5856-66.  [Epub 2013 Sep 19] PMID: 24052019.

Jung D, York JP, Wang L, Yang C, Zhang A, Francis HL, Webb P, McKeehan WL, Alpini G, Lesage GD, Moore DD, Xia X. (2013) FXR-induced secretion of FGF15/19 inhibits CYP27 expression in cholangiocytes through p38 kinase pathway.  Pflugers Arch. [Epub 2013 Sep 26]  PMID: 24068255

Luo Y, Yang C, Ye M, Jin C, Lee MH, Yeung SCJ, McKeehan WL (2013) Deficiency of metabolic regulator FGFR4 delays breast cancer progression through systemic and microenvironmental metabolic alterations.  Cancer Metab. 2013 Nov 25;1(1):21.  PMID: 24279986.

Luo Y, McKeehan WL (2013) Stressed liver and muscle call on adipocytes with FGF21. Front. Endocrinol. 4:194. PMID: 24385972

Publications 2014

Wang F, Luo Y and McKeehan WL  (2014) The FGF Signaling Axis in Prostate Tumorigenesis  In:  E. Gelmann, C. Sawyers and F. Rauscher, eds. Molecular Oncology: Causes of Cancer and Targets for Treatment, pp190-203, Cambridge University Press (Academic Press)

Shoji K, Teishima J, Hayashi T, Ohara S, McKeehan WL, Matsubara A.  (2014) Restoration of fibroblast growth factor receptor 2IIIb enhances the chemosensitivity of human prostate cancer cells. Oncol Rep. 2014 Jul;32(1):65-70. doi: 10.3892/or.2014.3200. Epub 2014 May 20. PMID: 24839986

Fuentes-Mattei E, Velazquez-Torres G, Phan L, Zhang F, Chou P-C, Shin J-H, Choi HH, Chen J-S, Zhao R, Chen J, Gully C, Carlock C, Qi Y, Zhang Y, Wu Y, Esteva FJ, Luo Y, McKeehan WL, Ensor J, Hortobagyi GN, Pusztai L, Symmans WF, Lee M-H, Yeung S-C J.  Obesity induces transcriptomic changes enhancing cancer hallmarks of estrogen receptor-positive breast cancer. J Natl Cancer Inst. 2014 Jun 23;106(7). pii: dju158. doi: 10.1093/jnci/dju158. Print 2014 Jul.PMID: 24957076

Wang C., C. Yang, J. YF Chang, Y. Li, C. Jin, Y. Luo, P. You, X. Li, W. L. McKeehan, and F. Wang (2014) Hepatocyte FRS2a is Essential for the Endocrine Fibroblast Growth Factor to Limit the Amplitude of Bile Acid Production Induced by Prandial Activity.  Curr Mol Med. 2014 Jul 23. [Epub ahead of print] PMID: 25056539

Wan, X., P. G. Corn, J. Yang, N. Palanisamy, M. W. Starbuck, E. Efstathiou, E. M. L Tapia, A. Zurita, A. Aparicio, M. K. Ravoori, E. S. Vazquez, D. Robinson, Y-M Wu, X. Cao, M. Lyer, W. McKeehan, V. Kundra, F. Wang, P. Troncoso, A. M. Chinnaiyan, C. J. Logothetis, N. M. Navone1 (2014) Prostate cancer cell–bone cell cross-talk via FGFR1 mediates dovitinib antitumor activity in men with bone metastases. Science Translational Medicine (in press)


For complete list of publications, go to PubMed (search: mckeehan wl).

Last edited by: wmckeehan 07/31/2014

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