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Dr. Margaret J. Wheelock

Title: Professor
Director Nebraska Center for Cellular Signaling

Address
Room: 12726A
987696 Nebraska Medical Center
University of Nebraska Medical Center
Omaha, NE 68198-7696


Oral Biology Department


Telephone: (402) 559-3892
Fax: (402) 559-3888
email: mwheelock@unmc.edu

Education:

• B.S. (Microbiology), University of Minnesota
• Ph.D. (Major: Cell Biology; Minor: Biochemistry), University of Minnesota

Teaching Responsibilities:

• Course Instructor, Advanced Oral Biology (OBIO 855)
• Course instructor, BIOC 880, PAMM 880, PHARM 880, PHSCI 880 "Principles and Methodologies in Cancer Research"

Research Interests:

• Our laboratory is interested in how cells interact with one another to form the three dimensional structure of a tissue. We are particularily interested in a family of proteins known as the cadherins. The cadherin family of proteins mediate the calcium-dependent interactions between cells that have been shown to be critical in cell sorting events that serve to form the various tissues during embryonic development. Cadherins are the transmembrane component of the adherens junction and interact homophilically in the extracellular space. The cytoplasmic domain of the cadherin interacts with a group of proteins called catenins that serve to link the cadherin to the cytoskeleton. Thus, the cadherin/catenin complex forms connections not only between two cells extracellularly but also coordinates cooperative cellular movements by linking together the cytoskeletal elements of two cells.
• The projects in our laboratory are designed to study the structure and function of the cadherin/catenin complex.
• One project is to determine which domains of the catenins allow them to associate with cadherin and thus become part of an adherens junction. In addition, we are attempting to understand how the cadherin/catenin complex is associated with the cytoskeleton. Our approach is to engineer fragments of the catenins, transfect these into tissue culture cells and determine which protein-protein interactions are retained.
• A second project is to unravel the signal transduction pathways involved in formation and activity of the cadherin/catenin adhesion complex. The cadherins have been implicated in the wnt (or wingless) signaling pathway which also involves APC and the transcription factor, Lef-1. Wnt-1 and APC are both known tumor-associated proteins, thus, one hypothesis is that cadherin involvement in tumorigenesis may involve not only physical disruption of cellular interactions but also important signaling events.
• A third project is to understand the role cadherins play in human pancreatic cancer. Our hypothesis is that some pancreatic cancer cells turn on the expression of an inappropriate cadherin. The expression of this molecule results in decreased cell-cell adhesion and increased cell motility and invasion. We have evidence that expression of N-cadherin by human cancer cells results in tumors that are highly metastatic and we are testing this in an orthotopic mouse model for pancreatic cancer.

Current Grants:

• Source: National Institutes of HealthID number: RO1 GM51188 (Wheelock, MJ, PI)Title: Aspects of cadherin/catenin complexesPeriod of support: 08/01/94-7/31/10The major goals of this project are to define the roles cadherins and catenins play in cell-cell adhesion, both as structural components of the adherens junction and as signaling molecules.
• Source: National Institutes of HealthID number: P20 RR18759 (Wheelock, MJ, PI)Title: Nebraska Center for Cellular SignalingPeriod of support: 07/01/08-6/30/13 This is a CoBRE grant, which establishes a center for cellular signaling that will function to bring together senior investigators to serve as mentors for junior investigators. Five junior investigator projects are funded on this grant and the goal is to assist these investigators in securing independent funding for their work.

Recent Publications:

• Curtis, M.W., Johnson, K.R. and Wheelock, M.J. E-cadherin/catenin complexes are formed cotranslationally in the endoplasmic reticulum/Golgi compartments. Cell Commun Adhes 15(4):365-78, 2008 Nov. PMID: 18937087 PubMed - in process
• Mandal, S., Johnson, K.R. and Wheelock, M.J. TGF-beta induces formation of F-actin cores and matrix degradation in human breast cancer cells via distinct signaling pathways. Exp Cell Res Epub ahead of print 2008 Sep 26. PMID: 18848540 PubMed - as supplied by publisher
• Keim, S.A., Johnson, K.R., Wheelock, M.J. and Wahl III, J.K. Generation and characterization of monoclonal antibodies against the proregion of human desmoglein-2. Hybridoma 2008 (In Press)
• Shintani, Y., Fukumoto, Y., Chaika, N., Svoboda, R., Wheelock, M.J. and Johnson, K.R. Collagen I-mediated up-regulation of N-cadherin requires cooperative signals from integrins and discoidin domain receptor 1. J Cell Biol 180:1277-89, 2008.
• Wheelock, M.J., Shintani, Y., Maeda, M., Fukumoto, Y. and Johnson, K.R. Cadherin switching. J Cell Sci 121:727-35, 2008.
• Shintani, Y., Fukumoto, Y., Chaika, N., Grandgenett, P.M., Hollingsworth, M.A., Wheelock, M.J. and Johnson, K.R. ADH-1 suppresses N-cadherin-dependent pancreatic cancer progression. Int J Cancer 122:71-7, 2008.
• Fukumoto, Y., Shintani, Y., Reynolds, A.B., Johnson, K.R. and Wheelock, M.J. The regulatory or phosphorylation domain of p120 catenin controls E-cadherin dynamics at the plasma membrane. Exp Cell Res 314:52-67, 2008.
• Shintani, Y., Maeda, M., Chaika, N., Johnson, K.R. and Wheelock, M.J. Collagen I promotes epithelial-to-mesenchymal transition in lung cancer cells via transforming growth factor-beta signaling. Am J Respir Cell Mol Biol 38:95-104, 2008.
• Theisen, C.S., Wahl, J.K., Johnson, K.R. and Wheelock, M.J. NHERF Links the N-cadherin/catenin complex to the PDGF receptor to modulate the actin cytoskeleton and regulate cell motility. Mol Biol Cell 18:1220-32, 2007.
• Pyo, S.W., Hashimoto, M., Kim, Y.S., Kim, C.H., Lee, S.H., Johnson, K.R., Wheelock, M.J. and Park, J.U. Expression of E-cadherin, P-cadherin and N-cadherin in oral squamous cell carcinoma: Correlation with the clinicopathologic features and patient outcome. J Craniomaxillofac Surg 35:1-9, 2007.
• Curtis, M.W., Ly, Q.P., Wheelock, M.J. and Johnson, K.R. Evidence that the V832M E-Cadherin germ-line missense mutation does not influence the affinity of alpha-catenin for the cadherin/catenin complex. Cell Commun Adhes 14:45-55, 2007.
• Maeda, M., Shintani, Y., Wheelock, M.J. and Johnson, K.R. SRC activation is not necessary for TGF-beta- mediated EMT in mammary epithelial cells; PP1 directly inhibits TGF-beta receptors l and ll. J Biol Chem 281:59-68, 2006.
• Shintani, Y., Wheelock, M.J. and Johnson, K.R. PI3K-Rac1-JNK signaling mediates collagen-induced cell scattering and up-regulation of N-cadherin expression in mouse mammary epithelial cells. Mol Biol Cell 17:2963-75, 2006.
• Maeda, M., Johnson, E., Mandal, S.H., Lawson, K.R., Keim, S.A., Svoboda, R.A., Caplan, S., Wahl, J.K. III, Wheelock, M.J. and Johnson, K.R. Expression of inappropriate cadherins by epithelial tumor cells promotes endocytosis and degradation of E-cadherin via competition for p120ctn. Oncogene 25:4595-604, 2006.
• Shintani Y., Hollingsworth, M.A., Wheelock M.J., and Johnson K.R. Collagen I promotes metastasis in pancreatic cancer by activating c-Jun NH(2)-terminal kinase 1 and up-regulating N-cadherin expression. Cancer Res 66:11745-53, 2006.
• Shintani, Y., Wheelock, M.J. and Johnson, K.R. Phosphoinositide-3 kinase-rac1-c-jun NH2-terminal kinase signaling mediates collagen I-induced cell scattering and up-regulation of N-cadherin expression in mouse mammary epithelial cells. Mol Biol Cell 17:2963-2975, 2006.
• Jaggi, M., Rao, P.S., Smith, D.J., Wheelock, M.J. and Johnson, K.R., Hemstreet, G.P. and Balaji, K.C., E-cadherin phosphorylation by protein kinase D1/protein kinase CM is associated with altered cellular aggregation and motility in prostate cancer. Cancer Res 65:483–92, 2005.
• Maeda, M., Johnson, K.R. and Wheelock, M.J. Cadherin switching: Essential for behavioral but not morphological changes in epithelial to mesenchymal transition. J Cell Sci 118:873-87, 2005.
• Kim, Y.J., Sauer, C., Testa, K., Wahl, J.K., Svoboda, R.A., Johnson, K.R., Wheelock, M.J. and Knudsen, K.A. Modulating the strength of cadherin adhesion: evidence for a novel adhesion complex. J Cell Sci 118:3883-94, 2005.
• Knudsen, K.A. and Wheelock, M.J. Cadherins and the mammary gland. J Cell Biochem 95:488-96, 2005.
• Knudsen, K.A., Sauer, C.K., Johnson, K.R. and Wheelock, M.J. Effect of N-cadherin misexpression by the mammary epithelium in mice. J Cell Biochem 95:1093-107, 2005.
• Kim, Y.J., Johnson, K.R. and Wheelock, M.J. N-cadherin-mediated cell motility requires cis dimers. Cell Commun Adhes 12:23-39, 2005.
• Maeda, M., Shintani, Y., Wheelock, M.J. and Johnson, K.R. SRC activation is not necessary for transforming growth factor (TGF)-beta-mediated epithelial to mesenchymal transition (EMT) in mammary epithelial cells. PP1 directly inhibits TGF-beta receptors I and II. J Biol Chem 281:59-68, 2005.
• Johnson. E., Theisen, C.S., Johnson, K.R. and Wheelock, M.J. R-cadherin influences cell motility via Rho family GTPases. J Biol Chem 279:31041-31049, 2004.
• Wheelock, M.J. and Johnson, K.R. Cadherins as modulators of cellular phenotype. Annu Rev Cell Dev Biol 19: 207-235, 2003.
• Wheelock, M.J. and Johnson, K.R. Cadherin-mediated cellular signaling. Curr Opin Cell Biol 15:509-514, 2003.
• Wen Y., Caffrey T.C., Wheelock M.J., Johnson, K.R. and Hollingsworth M.A. Nuclear association of the cytoplasmic tail of MUC1 and -catenin. J Biol Chem 278:38029-38039, 2003.
• Becker, K.F., Kremmer, E., Eulitz, M., Schulz, S., Mages, J., Handschuh, G., Wheelock, M.J., Cleton-Jansen, A.M., Hofler, H. and Becker, I. Functional allelic loss detected at the protein level in archival human tumours using allele-specific E-cadherin monoclonal antibodies. J Pathol 197:567-574, 2002.
• Govindarajan, R., Sumin, Z., Song, X.H., Guo, R.J., Wheelock, M.J., Johnson, K.R. and Mehta, P.P. Impaired trafficking of connexins in androgen-independent human prostate cancer cell lines and its mitigation by alpha-catenin. J Biol Chem 277:50087-50097, 2002.
• Jaggi, M., Wheelock, M.J. and Johnson, K.R. Differential displacement of classical cadherins by VE-cadherin. Cell Commun Adhes 9:103-115, 2002.
• Wheelock, M.J., Peralta Soler, A. and Knudsen, K.A. Cadherin junctions in mammary tumors. J Mammary Gland Biology Invited review 6:275-285, 2001.
• Hakuno, M., Akiyama, M., Shimizu, H., Wheelock, M.J. and Nishikawa, T. Upregulation of P-cadherin expression in the lesional skin of pemphigus, Hailey-Hailey disease and Darier disease. J Cutan Pathol 28:277-281, 2001.
• Reyes-Muigica, M., Meyerhardt, J.A., Rzasa, J., Johnson, K.R., Wheelock, M.J., Rimm, D.L., and Reale, M.A. Truncated DCC reduces N-cadherin/catenin expression and calcium dependent cell adhesion in neuroblastoma cells. Lab Invest 81:201-210, 2001.
• Puch, S., Arneanu, S., Kibler, C., Johnson, K.R., Muller, C.A., Wheelock, M.J. and Klein, G. N-cadherin is developmentally regulated and functionally involved in early hematopoietic cell differentiation. J Cell Science 114:1567-1577, 2001.
• Thoreson, M.A., Anastasiadis, P.Z., Daniel, J.M., Ireton, R.C., Wheelock, M.J., Johnson, K.R., Hummingbird, D.K. and Reynolds, A.B. Selective uncoupling of p120 (ctn) from E-cadherin disrupts strong adhesion. J Cell Biol 148:189-202, 2000.
• Proby, C.M., Ohta, T, Suzuki, H., Koyasu, S., Gamou, S., Shimizu, N., Wahl, J.K., Wheelock, M.J., Nishikawa, T. and Amagai, M. Development of chimeric molecules for recognition and targeting of antigen-specific B cells in Pemphigus Vulgaris. Br J Dermatol 142:321-330, 2000.
• Vallorosi, C.J., Day, K.C., Zhuo, X., Rashid, M.G., Rubin, M.A., Johnson, K.R., Wheelock, M.J. and Day, M.L. Truncation of the β-catenin binding domain of E-cadherin precedes epithelial apoptosis during prostate and mammary involution. J Biol Chem 275:3328-3334, 2000.
• Islam, S., Kim, J.B., Trendel, J., Wheelock, M.J. and Johnson, K.R. Vimentin expression in human squamous carcinoma cells: Relationship with phenotypic changes and cadherin based cell adhesion. J Cell Bioch 78:141-150, 2000.
• Wahl, J.K., Sacco-Bubulya, P.A., Sadler, T.M., Johnson, K.R. and Wheelock, M.J. The amino and carboxyl-terminal tails of β-catenin prevent its association with desmoglein 2. J Cell Sci 113:1735-1745, 2000.
• Knudsen, K.A., Lin, C.Y., Johnson, K.R., Wheelock, M.J., Keshgegian, A.A. and Peralta Soler. Lack of correlation between serum levels of E- and P-cadherin fragments in the presence of breast cancer. Human Pathology 31:961-965, 2000.
• Wu, H., Wang, Z.H., Yan, A., Lyle, S., Fakharzadeh, S., Wahl, J.K., Wheelock, M.J., Uitto, J., Amagai, M. and Stanley, J.R. Autoantigen compensation: Novel therapy for an autoantibody-mediated disease suggested by neonatal resistance to pemphigus foliaceus. New Engl J Med 343:31-35, 2000.
• Hakuno, M., Shimizu, H., Akiyama, M., Amagai, M., Wahl, J.K., Wheelock, M.J. and Nishikawa. T. Dissociation of intra- and extracellular domains of desmosomal cadherins and E-cadherin in Hailey-Hailey disease and Darier's disease. Br J Dermatol 142:702-111, 2000.
• Kim, J.-B., Islam, S., Kim, Y. J., Prudoff, R.S., Sass, K.M., Wheelock, M.J. and Johnson K.R. N-cadherin extracellular repeat 4 mediates epithelial to mesenchymal transition and increased motility. J Cell Biol 151:1193-1205, 2000.