news, events, and lectures | postdoctoral programs
predoctoral programs | faculty | university community

faculty

Maria A. Kukuruzinska Professor 715 Albany Street, Evans 4, room 428, Boston, MA 02118-2394 617/638-4859 (tel.) mkukuruz@bu.edu

education

Ph.D. Johns Hopkins University, 1983
Postdoctoral Training: Massachusetts Institute of Technology, 1984-1988


research description

Work in my laboratory examines how the metabolic pathway protein N-glycosylation guides cell-cell adhesion in tissue development and cancer. Our studies with cultured epithelial cells have shown that N-glycosylation of E-cadherin, a major epithelial cell-cell adhesion receptor that forms adherens junctions (AJs), affects the recruitment of key regulatory components to AJs and their association with the actin cytoskeleton. Among them is PP2A phosphatase, a stabilizer of AJs but an inhibitor of tight junctions (TJs). By inhibiting the association between PP2A and AJs, E-cadherin N-glycans promote the interaction between PP2A and selected components of TJ thus interfering with the TJ assembly. Studies are underway to elucidate how changes in E-cadherin N-glycosylation drive reorganization of AJs and TJs and how this impacts cellular signaling and function.

A related study examines how dysregulation of cellular N-glycosylation promotes the development and progression of oral squamous cell carcinoma (OSCC). OSCC is characterized by aberrantly high cellular N-glycosylation that correlates with excessive N-glycosylation of E-cadherin, unstable AJs and lack of TJs. Partial inhibition of cellular N-glycosylation in oral cancer cell lines with siRNA to the DPAGT1 gene, a key regulator of protein N-glycosylation, leads to reduced N-glycosylation of E-cadherin and to the stabilization of AJs and TJs. This drives the reversal of malignant cell morphology to epithelial phenotype. Current studies examine E-cadherin scaffolds and downstream signaling events that lead to the loss of E-cadherin’s tumor suppressive function in OSCC.

Another project investigates the role of E-cadherin junctions in the mouse submandibular gland (SMG) development using SMG organ culture coupled with E-cadherin function-blocking antibodies and siRNA-based E-cadherin gene silencing. Using these approaches we have shown that through the organization of different types of junctions, E-cadherin regulates major events during SMG morphogenesis including proliferation of acinar and ductal progenitors, formation of new buds, as well as rearrangements and survival of cells during tubulogenesis. Interestingly, E-cadherin junctions in the acinar progenitor cell layer are stabilized through indirect scaffolds with a3b1 integrin. Our ongoing studies focus on the investigation of the signaling pathways affected by different types of E-cadherin junctions during SMG development.

representative publications

Nita-Lazar, M., Noonan, V., Rebustini, I., Walker, J., Menko, A.S. and Kukuruzinska, M.A. (2008) Aberrant N-glycosylation of E-cadherin Drives Cellular Discohesionin Oral Cancer. (submitted).

Walker, J.L., Menko, A.S., Khalil, S., Rebustini, I., Hoffman, M.P., Kreidberg, J.A. and Kukuruzinska, M.A. (2008) Diverse Roles of E-cadherin in the Morphogenesis of the Submandibular Gland: Insights into the Formation of Acinar and Ductal Structures. (submitted).

Liwosz, A., Lei, T-L., and Kukuruzinska, M.A. (2006). N-glycosylation Affects Molecular Organization and Stability of E-cadherin Junctions. J Biol Chem 281(32), 23138-49.

Mendelsohn, R.D., Helmerhorst, E., Cipollo, J.F. and Kukuruzinska, M.A. (2005). A Hypomorphic Allele of the First N-glycosylation Gene, ALG7, Causes Mitochondrial Defects in Yeast. Biochim Biophys Acta. 1723, 33-44.

Rex, S., Kukuruzinska, M. A. and Istfan, N. W. (2002). Inhibition of DNA Replication by Fish Oil-treated Cytoplasm is Counteracted by Fish Oil-treated Nuclear Extract. Am J Physiol Cell Physiol 283(5): C1365-75.

Menko, A. S., Zhang, L., Schiano, F., Kreidberg, J. A. and Kukuruzinska, M. A. (2002). Regulation of Cadherin Junctions During Mouse Submandibular Gland Development. Dev Dyn 224(3): 321-33.

Klebl, B, Kozian, D., Leberer, E. and Kukuruzinska, M. A. (2001). A Comprehensive Analysis of Gene Expression Profiles in a Yeast N-Glycosylation Mutant. Biochem Biophys Res Commun 286(4): 714-20.

Menko, A. S., Kreidberg, J. A., Ryan, T. T., Van Bockstaele, E. and Kukuruzinska, M. A. (2001). Loss of alpha3beta1 Integrin Function Results in an Altered Differentiation Program in the Mouse Submandibular Gland. Dev Dyn 220(4): 337-49.

Fernandes, R. P., Cotanche, D. A., Lennon-Hopkins, K., Erkan, F.Menko, A. S. and Kukuruzinska, M. A. (1999). Differential Expression of Proliferative, Cytoskeletal, and Adhesive Proteins During Postnatal Development of the Hamster Submandibular Gland. Histochem Cell Biol 111(2): 153-62.

Kukuruzinska, M. A. and K. Lennon-Hopkins (1999). ALG Gene Expression and Cell Cycle Progression. Biochim Biophys Acta 1426(2): 359-72.