Last Updated: 3/22/2010

Research Interests
Epithelial tissues are affected in many cancers. It is a tenet of modern molecular medicine that to understand the abnormal cell behaviors in cancer we must understand normal cell behavior. The recognition that all eukaryotic cells use similar cellular machinery has driven scientists to adopt a functional genomics approach to understanding the roles of key proteins involved in human diseases. Function of these proteins is rapidly examined in simple model systems like yeast or Drosophila, where one can combine molecular genetics with cell biology and biochemistry and thus capitalize on the speed of model systems and their synergy with vertebrate cell biology. Results of these analyses can be immediately applied to human cells.

Our entrée into studying underlying causes of epithelial tumors was the protein Armadillo/ß-catenin, which plays roles in colon and other cancers (reviewed in Peifer and Polakis, 2000). We demonstrated that Armadillo/ß-catenin is a key component of cell-cell adherens junctions, where it joins transmembrane cadherins to alpha-catenin and the actin cytoskeleton (reviewed in Gates and Peifer, 2005). ß-catenin and adherens junctions are essential for maintaining epithelial organization, for cell polarity, and for normal embryonic development. Disruption of cell adhesion is a hallmark of most metastatic tumors. ß-catenin plays a separate role in transducing Wnt cell-cell signals. In this role, it forms a heterodimer with the TCF DNA-binding protein, creating a bipartite transcription factor that regulates Wnt target genes (van de Wetering et al., 1997). In contrast, in cells where Armadillo/ß-catenin levels are low, TCF represses Wnt target genes, using Groucho family proteins as a co-repressors (Cavallo et al., 1998). One of our goals is to understand at the biochemical level the roles of Armadillo/ß-catenin. They and their interactors are potential drug targets, via small molecule inhibitors of ß-catenin action in carcinogenesis. As part of this effort, in collaboration with colleagues at the Weizmann Institute, we analyzed the sequence determinants required for the binding of Armadillo/ß-catenin to its partners (Simcha et al., 2001)—this and similar information can be used by pharmaceutical companies as they design inhibitors to the Wnt pathway. This work was funded by the U.S. Army Breast Cancer Program, via IDEA and Career Development Awards.

Armadillo/ß-catenin 's role in signal transduction is regulated by regulating its protein stability. The machinery for targeting it for destruction includes the tumor suppressor protein APC, which is mutated in most cases of familial and sporadic colon cancer. One focus of the lab is to APC reveal APC's mechanism of action. We have developed a fly model system with which to study APC function (McCartney et al., 1999). We used this system to identify a novel function for APC family proteins in linking the mitotic spindle to the cell cortex, a role that may have relevance for tumor progression in human cancer (McCartney et al., 2001). In addition, we have explored the functional overlap between the two fly APC family members (Akong et al., 2002), as a model for the overlap in function between the two human APCs. We are now focused on the mechanism of action of APC in the destruction complex (McCartney et al. 2006, and are using site-directed alleles to test different hypotheses for APC function. We are combining work on the Drosophila system with work in cultured colon cancer cells.

Wnt signaling and APC function have also been implicated in both normal and cancer stem cells. We have used the fly model to test hypotheses of APC function in neural stem cells and neurons (Hayden et al., 2007; Rusan et al., 2008). This work was initially funded by the Human Frontiers Science Program (as a collaboration with Hans Clevers of the Netherlands and Ken Kinzler of Johns Hopkins), and now is funded by a second RO1 to our lab from the NIH. Brooke McCartney, the postdoc who initiated this project, was awarded a Leukemia and Lymphoma Society Senior Fellowship.

A second focus of our lab is to examine the regulation of cell adhesion during embryonic development, and how this may be disrupted during cancer metastasis. In the course of this work, we have developed a model system in which to study the oncogene Abl, mutated in two of the most common forms of human leukemia. We found that Abl regulates cell adhesion and cell shape changes during morphogenesis, and that it does so via Enabled, a modulator of actin dynamics (Grevengoed et al., 2001; Grevengoed et al. 2003; Fox and Peifer, 2007; Stevens et al., 2008). This work has also been funded by the NIH and the Leukemia and Lymphoma Society, We are continuing to examine the roles of Abl and Ena, and are also investigating other candidate adhesive regulators including the formin Diaphanous (Homem and Peifer, 2008) and the protein Canoe/AF-6, work carried out by Jessica Sawyer, an American Heart Association Pre-doctoral Fellow (Sawyer et al, 2009). Another property of epithelial cells that is disrupted during oncogenesis is cell polarity. This is critical for normal tissue architecture and is disrupted in many late stage tumors. We have placed cadherins in a polarity pathway downstream of the protein Bazooka/Par-3, and are examining how events upstream and downstream of these players are coordinated to establish and maintain polarity (Harris and Peifer, 2004, 2005, and 2007).

Publications
Rogers,G.C., Rusan, N.M., Roberts,D.M., Peifer, M., and Rogers, S.L. (2009) The SCFSlimb ubiquitin-ligase regulates Plk4/Sak levels to block centriole reduplication. Journal of Cell Biology 184, 225-239.

Sawyer, J.K., Harris, N.J., Slep, K.C., Gaul, U., and Peifer, M. (2009) The Drosophila afadin homolog Canoe regulates linkage of the actin cytoskeleton to adherens junctions during apical constriction. Journal of Cell Biology 186:57-73

Rusan, N.M., Akong, K., and Peifer, M. (2008). Putting the model to the test: are APC proteins essential for neuronal polarity, axon outgrowth and axon targeting? Journal of Cell Biology 183:203-12.

Homem, C.C.F., and Peifer, M. (2008) Diaphanous regulates myosin and adherens junctions to control 
cell contractility and protrusive behavior during morphogenesis. Development 135, 1005-1018.

Stevens, T L., Rogers, E M., Koontz, L. M. , Fox, D. T., Homem, C. C.F., Nowotarski, S. H., Artabazon, N. B., and Peifer, M. (2008). Using Bcr-Abl to examine mechanisms by which Abl kinase regulates morphogenesis in Drosophila. Molecular Biology of the Cell 19 378-393.

Harris, T.J.C., and Peifer, M. (2007). aPKC controls microtubule organization to balance adherens junction symmetry and planar polarity during development. Developmental Cell, 12 727-738.

Fox, D.T., and Peifer, M. (2007). Abelson kinase and RhoGEF2 regulate actin organization during cell constriction in Drosophila. Development 134, 567-578

Hayden, M.A., Akong, K., and Peifer, M. (2007). Novel roles for APC family members and Wingless/Wnt signaling during Drosophila brain development. Developmental Biology 305, 358-376

McCartney, B.M., Price, M.H., Webb, R., , Hayden, M.A., Holot, L., Zhou, M, Bejsovec, A., and Peifer, M. (2006). Testing hypotheses for the functions of APC family proteins using null and truncation alleles in Drosophila. Development 133 2407-2418.

Gates, J., and Peifer, M. (2005). Can 1000 reviews be wrong? Actin, alpha-catenin and Adherens Junctions. Cell 123, 769-772.


Harris, T.J.C., and Peifer, M. (2005). The positioning and segregation of apical cues during epithelial polarity establishment in Drosophila. Journal of Cell Biology 170, 813-823.

Harris, T.J.C., and Peifer, M. (2004). Adherens junction-dependent and -independent steps in the establishment of epithelial cell polarity in Drosophila. Journal of Cell Biology165, 135-147.

Grevengoed, E.E., Fox, D.T., Gates, J., and Peifer, M. (2003). Balancing different types of actin polymerization at distinct sites: Roles for Ableson kinase and Enabled. Journal of Cell Biology 163, 1267-1280.

Akong, K., Grevengoed, E.E., Price, M.H., McCartney, B.M., Hayden, M.A., DeNofrio, J.C., and Peifer, M. (2002). Drosophila APC2 and APC1 play overlapping roles in Wingless signaling in the embryo and imaginal discs. Developmental Biology 250, 91-100.

McCartney, B.M., McEwen, D.G., Grevengoed,, E., Maddox, P., Bejsovec, A., Peifer, M. (2001) Drosophila APC2 and Armadillo participate in tethering mitotic spindles to cortical actin. Nature Cell Biology 3, 933-938.

Grevengoed, E.E., Loureiro, J.J., Jesse, T.L., and Peifer, M. (2001). Abelson kinase regulates epithelial morphogenesis in Drosophila. Journal of Cell Biology 155, 1185-1197.

Simcha, I., Kirkpatrick, C., Sadot, E., Shtutman, M. Polevoy, G., Geiger, B., Peifer, M., and Ben-Ze’ev, A. (2001). Cadherin Sequences that Inhibit ß-catenin Signaling: a Study in Yeast and Mammalian Cells. Molecular Biology of the Cell 12: 1177-88.

McCartney, B., Dierick, H.A., Kirkpatrick, C., Moline, M.M., Baas, A., Peifer, M., and Bejsovec, A. (1999). Drosophila APC2 is a cytoskeletally-associated protein that regulates Wingless signaling in the embryonic epidermis. J. Cell Biol. 146, 1303-1318.

Peifer, M., and Polakis, P. (2000). Wnt signaling in oncogenesis and embryogenesis: A look outside the nucleus. Science 287, 1606-1609.

Cavallo, R. A., Cox, R. T., Moline, M. M., Roose, J., Polevoy, G. A., Clevers, H., Peifer, M. and Bejsovec, A. (1998). Drosophila TCF and Groucho interact to repress Wingless signaling activity. Nature 395, 604-608.

E-mail: peifer@unc.edu
Telephone: (919) 962-2271
FAX: (919) 962-1625
Address: 521 Fordham Hall, CB# 3280, Biology Chapel Hill, NC 27599
URL: www.bio.unc.edu/faculty/peifer/

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