Maria A. Kukuruzinska
Professor, Department of Molecular & Cell Biology
Associate Dean for Research
72 East Concord Street
Boston, MA 02118-2394 USA
PhD, Johns Hopkins University, 1983
Post-doctoral training: Massachusetts Institute of Technology, 1984–1988
Research Activities and Description
The long-term goal of my work is to elucidate the regulatory mechanisms underlying the interactions between the metabolic pathway of protein N-glycosylation and intercellular adhesion in tissue development and disease.
Cross Talk Between Protein N-glycosylation, E-cadherin-mediated Cell-Cell Adhesion, and Canonical Wnt Signaling. Studies in my laboratory have unveiled a critical role for N-glycosylation in the function of E-cadherin, a major epithelial cell-cell adhesion receptor that forms adherens junctions (AJs). They have shown that N-glycosylation affects the maturity of AJs and the assembly of tight junctions (TJs), as well as cytoskeletal dynamics. On a molecular level, the N-glycosylation status of E-cadherin is controlled by the DPAGT1 gene, the first gene in the N-glycosylation pathway and its key regulator. At the same time, E-cadherin junctions regulate DPAGT1 expression, indicating the existence of a bidirectional feedback loop between the metabolic pathway of protein N-glycosylation and cell-cell adhesion. Current studies in my laboratory are aimed at elucidating the molecular mechanism via which AJs regulate N-glycosylation.
Mechanisms Underlying Salivary Gland Development. Another major project in my laboratory focuses on the key mechanisms that drive submandibular gland (SMG) development. We have shown that E-cadherin regulates major events during SMG morphogenesis, including proliferation of acinar and ductal progenitors, formation of new buds and survival of ductal progenitors during tubulogenesis. E-cadherin also plays an important role in the planar cell polarity pathway that drives ductal axis extension during SMG morphogenesis. These developmental functions of E-cadherin are regulated by N-glycosylation. Our ongoing studies focus on the molecular characterization of how N-glycosylation and E-cadherin impact acinar and ductal cell fate specification and drive the formation of mature SMG structures.
Molecular Basis of Oral Cancer. The conceptual framework of our mechanistic studies is being applied to investigation of the development and progression of oral cancer. Our recent work has shown that aberrant activation of cellular N-glycosylation promotes the development and progression of oral squamous cell carcinoma (OSCC). Partial inhibition of cellular N-glycosylation in oral cancer cell lines leads to the stabilization of intercellular adhesion, which then drives the mesenchymal to epithelial transition. Current studies examine the molecular basis of over-expression of DPAGT1 in OSCC and its relationship to the downstream signaling pathways that impact E-cadherin’s tumor suppressive function.
Molecular Basis of Sjogren’s Syndrome. Recently, we have initiated studies on Sjogren’s Syndrome (SS), an autoimmune disease that affects salivary and lacrimal glands. Although Sjogren’s disease has long been thought to be caused by lymphocytic infiltration, our recent work has suggested that defective intercellular adhesion is one of the underlying causes of this disease. To expedite the deciphering of the molecular basis of SS and to promote the development of new diagnostics, I co-founded an international collaboration, the Norwegian-United States Initiative on Sjogren’s Syndrome (NUSSIS), that brings together basic researchers and clinicians from the University of Oslo, University at Albany-SUNY, University of Florida, and Boston University School of Dental Medicine.
Sengupta PK, Bouchie MP, Nita-Lazar M, Yang H-Y and Kukuruzinska, MA. (2013). Coordinate regulation of N-glycosylation gene DPAGT1, canonical Wnt signaling and E-cadherin adhesion. J. Cell Sci., jcs.113035; 126, 484-496. Epub 2012 Nov 23. PMID: 23178939.
Liu, G., Kukuruzinska, MA. and Xu, X. (2013). Ror2 may be downregulated in oral squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol. 2013 Jul;116(1):120. doi: 10.1016/j.oooo. 2012. 12.018. Epub 2013 Mar 5. PMID: 23465658
Liu, G., Sengupta, P.K., Jamal, B., Yang, H-Y., Bouchie, M.P., Lindner, V., Varelas, X., and Kukuruzinska, M.A. (2013). N-glycosylation induces CTHRC1 protein and drives oral cancer cell migration. J Biol Chem. 288, 20217-27. Epub 2013 May 23. PMID: 23703614.
Enger, T.B., Samad-Zadeh, A., Bouchie, M.P., Skarstein, K., Galtung, H.K., Mera, T., Walker, J., Menko, A.S., Varelas, X., Faustman, D.L., Jensen, J.L., and Kukuruzinska, MA. (2013). The Hippo signaling pathway is required for salivary gland development and its dysregulation is associated with Sjogren’s syndrome. Lab Invest. 93, 1203-1218.
Jamal B, Sengupta PK, Gao Z, Nita-Lazar M, Amin B, Jalisi S, Bouchie MP and Kukuruzinska, MA. (2012). Aberrant Amplification of the Crosstalk between Canonical Wnt Signaling and N-glycosylation Gene DPAGT1 Promotes Oral Cancer. Oral Oncol., 48, 523-29. PMID: 22341307.
Sengupta, P. K., Bouchie, M. P., and Kukuruzinska, MA. N-glycosylation Gene DPAGT1 is a Target of the Wnt/Beta-catenin Signaling Pathway. J. Biol. Chem. 2010. Aug 6, [Epub adhead of print] (Selected for Research Highlights by Nature Chemical Biology, Oct 2010 and by Nature Functional Glycomics, Sept 2010).
Nita-Lazar, M., Rebustini, I., Walker, J., and Kukuruzinska, MA. Hypoglycosylated E-cadherin Promotes the Assembly of Tight Junctions Through the Recruitment of PP2A to Adherens Junctions. Exp. Cell Res. 2010. 316: 1871–1884.
Nita-Lazar, M., Noonan, V., Rebustini, I., Walker, J., Menko, A. S., and Kukuruzinska, MA. Overexpression of DPAGT1 Leads to Aberrant N-glycosylation of E-cadherin and Cellular Discohesion in Oral Cancer. Can. Res. 2009. 69: 5673–80.
Jamal, B. T., Nita-Lazar, M., Gao, Z., Amin, B., Walker, J., and Kukuruzinska, MA. N-glycosylation Status of E-cadherin Controls Cytoskeletal Dynamics Through the Organization of Distinct β-catenin- and γ-catenin-containing AJs. Cell Health Cytoskel. 2009. 1, 1–14. (Favorite author status)
Walker, J., Menko, A. S., Khalil, S., Rebustinin, I., Hoffman, M. P., Kreidberg, J. A., and Kukuruzinska, MA. Diverse Roles of E-cadherin in the Morphogenesis of the Submandibular Gland: Insights into the Formation of Acinar and Ductal Structures. Dev. Dyn. 2008. 237: 3128–41. (Editor’s Highlight, Mar 2009; Editor’s ArtPix, Jan 2009)