Oral Biology and Eppley Cancer Institute

• NAME/TRAINING:

        Margaret J. Wheelock, Ph.D.

University of Minnesota, B.S.-1977  Major: Microbiology
University of Minnesota, Ph.D.- 1982 Major: Cell Biology, Minor: Biochemistry
Postdoctoral Fellow, Wistar Institute, Philadelphia., PA

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• CONTACT INFORMATION:

Contact Name:	Margaret J. Wheelock, Ph.D.
Phone Number:	402-559-3892
e-mail address:	mwheelock@unmc.edu

• GRANT SUPPORT (last 3 years):

Agency:  NIH P20 RR18751	Period:  09/19/03 - 06/30/08
"Nebraska Center for Cellular Signaling"
Agency:  NIH  R01-GM 51188 “Aspects of cadherin/catenin complexes”	Period:  08/01/94 - 07/31/10
Agency: Nebraska Research Initiative "Cell adhesion proteins in cancers of the head and neck"	Period:  09/01/02-09/30/06

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• PUBLICATIONS (last 3-5 years):

Wahl, J.K. III , Kim, Y.J., Cullen, J.M., Johnson, K.R. and Wheelock, M.J.  2003.  N-cadherin/catenin complexes form prior to cleavage of the proregion and transport to the plasma membrane.  J. Biol. Chem. 278:17269-17276.

Katafiasz, B.J., Nieman, M.T., Wheelock, M.J., Johnson, K.R. 2003. Characterization of cadherin-24, a novel alternatively spliced type II cadherin. J. Biol. Chem. 278:27513-27519.

Wheelock, M.J. and Johnson, K.R.  2003. Cadherins as modulators of cellular phenotype.  Annu. Rev. Cell Dev. Biol. 19:207-235. 

Wheelock, M.J. and Johnson, K.R.  2003. Cadherin-mediated cellular signaling.  Curr. Opin. Cell Biol.  15:509-514.

Wen Y., Caffrey T.C., Wheelock M.J., Johnson K.R. and Hollingsworth M.A. 2003.  Nuclear association of the cytoplasmic tail of MUC1 and beta-catenin. J. Biol. Chem. 278:38029-38039.

Johnson. E., Theisen, C.S., Johnson, K.R. and  Wheelock, M.J. 2004. R-cadherin influences cell motility via Rho family GTPases.  J. Biol. Chem. 279:31041-31049. 

Jaggi, M., Rao, P.S., Smith, D.J., Wheelock, M.J., Johnson, K.R., Hemstreet, G.P. and Balaji, K.C.  2005.  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.

Maeda, M., Johnson, K.R. and Wheelock, M.J.  2005.  Cadherin switching:  Essential for behavioral but not morphological changes in epithelial to mesenchymal transition.  J. Cell Sci. 118:873-87.

Kim, Y.J., Sauer, C., Testa, K., Wahl, J.K., Svoboda, R.A., Johnson, K.R., Wheelock, M.J., Knudsen, K.A.  2005.  Modulating the strength of cadherin adhesion: evidence for a novel adhesion complex.  J Cell Sci. 118:3883-94.

Knudsen, K.A., Wheelock, M.J.  2005. Cadherins and the mammary gland.  J Cell Biochem. 95 :488-96.

Knudsen, K.A., Sauer, Ck, Johnson, K.R., Wheelock, M.J.  2005.  Effect of N-cadherin misexpression by the mammary epithelium in mice. J Cell Biochem. 95:1093-107. 

Kim, Y.J., Johnson, K.R., Wheelock, M.J. 2005.  N-cadherin-mediated cell motility requires cis dimers.  Cell Commun Adhes. 12:23-39.

Maeda, M., Shintani, Y., Wheelock, M.J., Johnson, K.R.  2006. SRC activation is not necessary for TGF-beta -mediated EMT in mammary epithelial cells; PP1 directly inhibits TGFbeta receptors l and ll. J Biol Chem. 281:59-68.

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. 2006.  Expression of inappropriate cadherins by epithelial tumor cells promotes endocytosis and degradation of E-cadherin via competition for p120^ctn.  Oncogene in press.

Shintani, Y., Margaret J. Wheelock, M.J. and Johnson, K.R.  2006. PI3K-Rac1-JNK signaling mediates collagen I-induced  epithelial to mesenchymal transition and up-regulation of  N-cadherin expression in mouse mammary epithelial cells.  Submitted.

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1988-1990	Hae Sun Kim  M.S. - Currently an assistant professor at Rutgers University.
1988-1992	Anuharada Rampalli  Ph.D. - Currently a scientist at Baxter in Chicago.
1991-1995	Jani Lewis Ph.D. - Currently an assistant professor at SUNY Geneseo.
1993-1996	Tammy McGranahan  M.S. - Currently a research technician.
1993-1998	Shahidul Islam  Ph.D. - Currently an assistant professor at Northwestern University
1994-1999	Marvin T. Nieman  Ph.D. - Currently a research assistant professor at University of Michigan.
1996-1999	Ryan Prudoff - Currently a medical student at Ohio University.
1993-2000	James Wahl  Ph.D. - Currently an assistant professor at UNMC.
1997-2003	Monty Johnson -  Currently a postdocotral fellow at Case Western.
1997-2002	Meena Jaggi  Ph.D.  Currently an assistant professor at University of South Dakota
2002-2005	Masato Maeda, M.D., Ph.D.  Currently a surgeon in Japan
2001-present	Chris Theisen - Currently a graduate student.
2004-present	Yasushi Shintani, M.D., Ph.D.  Currently a postdoctoral fellow in our lab

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• CURRENT RESEARCH PROJECTS:

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 catenins 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 cancer.  Our hypothesis is that some 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 aggressive.  Current projects focus on breast cancer, pancreatic cancer and oral cancer.

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• SPECIALIZED LABORATORY/CLINICAL RESEARCH RESOURCES:

Not Applicable

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