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FACULTY

Rytis Prekeris


Associate Professor

Rytis Prekeris, Associate Professor

Cell and Developmental Biology
Ph.D., East Carolina University - Greenville, 1997

Research Interest

The role of cell polarity during cell division, epithelial tissue morphogenesis and cancer cell metastasis


Contact​

Office Location: RC-1 South, Room 12112​

Mailing Address:

Mail Stop 8108​
12801 East 17th Avenue ​
Aurora, CO 80045

Phone: 303-724-3411 (ofc)
303-724-3410 (lab)
Fax: 303-724-3420
Email: Rytis.Prekeris@ucdenver.edu

Departmental Affiliations

Cell and Developmental Biology

Graduate Program Affiliations

Cell Biology, Stem Cells, and Development (CSD)
Biomedical Sciences Program (BSP)
Molecular Biology
Human Disease​

 

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ONGOING AND FUTURE RESEARCH

Molecular Mechanisms Regulating Cell Polarization and Protein Targeting 

My general research interest is to understand the mechanisms of cell polarization and the functional consequences of this polarization during development and cancerogenesis. In the last several years my laboratory has focused on three distinct but related projects: regulation and function of asymmetric cell division, mechanisms of cancer metastasis and regulation of epithelia polarization in vitro and in vivo. The latest findings and future directions for these projects are described below.

1. Molecular mechanisms of epithelial cells polarization. 

Epithelial cells are structurally and functionally polarized to transport specific molecules while maintaining a trans-epithelial barrier. This cellular asymmetry is essential for the proper functioning of epithelial tissues and depends on polarized endocytic transport routes. Additionally, epithelial cells coordinate their polarization with neighboring cells to form an apical lumen, a key step in the establishment of renal and gut architecture, and thereby function. Indeed, malfunctions in epithelial cell polarization and apical lumen formation are responsible for a variety of renal and intestinal disorders, such as polycystic kidney disease, renal tubular acidosis, microvilli inclusion disease and diabetes insipidus. This project aims to fill critical gaps in our understanding of epithelial cell biology, including what are the molecular mechanisms mediating coordinated formation of apical lumen during epithelia morphogenesis and function. 

Despite recent advances in our understanding of the mechanisms mediating lumen formation, many questions remains unanswered. How are endosomes targeted during apical lumen formation? How do cells establish the site of single apical lumen? Do the mechanisms of lumen formation established in vitro also apply to epithelial morphogenesis in vivo? Addressing these pivotal and unanswered questions forms the backbone of this project. This study is designed to analyze the machinery of apical lumen formation using in vitro (MDCK cells three dimensional cultures) and in vivo (zebrafish) models.


2. Regulation breast cancer metastasis.

 
Remodelling of the extracellular matrix (ECM) is a key process during tumor growth and metastasis and is mediated via formation of structures, known as invadopodia, and targeted secretion of enzymes, known as matrix metalloproteinases (MMPs). Invadopodia are actin-rich structures that degrade the ECM and have been shown to be important for tumor progression. MMP2/9 also have been shown to be enriched at the invadopodia and are known for their roles in breast tumor growth/metastasis. As a result, MMP2/9 have emerged as possible therapeutic targets. Unfortunately, clinical trials directly inhibiting MMP2/9 have proven ineffective, mostly due to adverse side effects and pre-existing high levels of secreted MMPs. It has been proposed that targeting the machinery specifically mediating MMP secretion at cancer cell invadopodia is more effective approach. However, little is known about targeted MMP2/9 secretion since most of the studies have focused on the mechanisms mediating ECM and cell adhesion and actin dynamics during metastasis. In contrast, very few studies have analysed the machinery mediating targeted MMP secretion in cancer cells in vitro and tested these mechanisms in vivo. The main goal of this project is to combine studies using basic cell and molecular biology techniques with more translational in vivo approaches to define and systematically analyse novel pathways that mediate targeted MMP transport and secretion during breast cancer metastasis. The strength of this project is combining of the unique expertise from my lab (cell biology and Rab GTPases), Dr. Paul Jedlicka (microRNA and pathology) and Dr. Tracy Lyons (breast cancer and xenograft assays) laboratories. This combination will allow us to comprehensively test these hypotheses in vitro and in vivo.

3. The role of midbodies in regulating cancer and stem cell proliferation.

 
Cytokinesis is the final stage of the cell cycle resulting in physical separation of daughter cells. At late mitosis, the mother cell divides by the formation of a cleavage furrow, leaving two daughter cells connected by a thin intercellular bridge (ICB). The resolution of this bridge, abscission, is mediated by coordinated action between specialized recycling endosomes and cytoskeleton. During ingression of the cleavage furrow, the central spindle microtubules are compacted to form the structure known as the midbody (MB). The MB is situated within the ICB, with the abscission usually occurring at one side of the MB. As a result of this one-sided (asymmetric) abscission, only one daughter cell inherits the post-mitotic MB. These post-mitotic MBs can then either accumulate in the cytoplasm or be degraded. Interestingly, recent studies have identified post-mitotic MBs as novel signaling platforms regulating stem cell fate and proliferation. Indeed, stem cells were shown to accumulate post-mitotic MBs and the induction of MB accumulation leads to reprogramming of cell fate and conversion to highly-proliferative stem cell-like phenotypes. Despite the importance of MBs in determining cell fate and proliferative capacity, the mechanisms that regulate asymmetric MB inheritance and post-mitotic degradation remains completely unknown. As the result, the main goal of this project is to identify the factors mediating MB inheritance and accumulation, and to test the role of these factors in regulating stem cell fate and differentiation.

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Schiel, J.A., Simon, G., Castle, D., Christine C.W., D., and Prekeris, R. (2012) FIP3-endosome mediated actin depolymerization and formation of the secondary ingression mediates ESCRT-III recruitment to the abscission site during cytokinesis. Nature Cell Biology. In Press.

Prekeris, R. (2012) The art of “Cut and Run”: the role of Rab14 GTPase in regulating N-cadherin shedding and cell motility. Developmental Cell. 22(9):909-910.

Prekeris, R. (2012) Making the final cut: the role of endosomes during mitotic cell division. Chapter in Book “Membrane Trafficking”.

Collins, L.L., Simon, G.S., Matheson, J., Wu, C., Miller, M.C., Otani, T., Yu, X., Prekeris, R., and G.W. Gould (2012) Rab11-FIP3 is a cell cycle-regulated phosphoprotein. BMC Cell Biology. 13(1):4.

Arras, L., Yang, I., Lackford, B., Riches, D., Prekeris, R., Freedman, J.H., Schwartz, D.A., and Alper, S. (2012) Spatiotemporal inhibition of innate immunity signaling by the TBC1D23 Rab-GAP. The Journal of Immunology. 188(6):2905-2913.

Willenborg, C., Jing, J., Wu, C., Matern, H., Burden, J., and Prekeris, R. (2011) FIP5/Rip11 and SNX18 Interaction Regulates Epithelial Lumen Formation. The Journal of Cell Biology. 195(1):71-86.

Schiel, J., Park, K., Morphew, M.K., Reid, E., Hoenger, A., and Prekeris, R. (2011) Coordinated Endocytic Membrane Fusion and Buckling-Induced Microtubule Severing Mediate Cell Abscission. Journal of Cell Science. 124:1411-1424.

Willenborg, C., and Prekeris, R. (2011) Apical protein transport and lumen morphogenesis in polarized epithelial cells. Bioscience Reports. 31(4):245-256.

Schiel, J. and Prekeris, R. (2010) Making the final cut: Mechanisms mediating the abscission step of cytokinesis. The Scientific World Journal. 10:1424-1434.

Hsu, VW and Prekeris, R. (2010) Mechanistic understanding of transport through the recycling endosome. Current Opinion in Cell Biology. 22(4):528-534.

Jing, J., Junutula. J.R., Wu, C., Burden, J., Peden, A.A., and R. Prekeris (2010) FIP1/RCP binding to Golgin-97 regulates retrograde transport from recycling endosomes to Trans-Golgi Network. Molecular Biology of the Cell. 21(17):3041-3053.

Jing, J., Wilson, G., Tarbutton, E., and R. Prekeris (2009) Rab11-FIP3 is a Rab11 and Arf6 binding proteins that regulates breast cancer motility by modulating actin cytoskeleton. European Journal of Cell Biology. 88(6):325-341.

Jing, J. and Prekeris, R. (2009) Polarized endocytic transport: the roles of Rab11 and Rab11-FIPs in regulating cell polarity. Histology and Histopathology: Cellular and Molecular Biology. 24(9):1171-1180.

Simon, G.C., E. Schonteich, C.C. Wu, D. Ekiert, A. Piekny, X. Yu, G.W. Gould, M. Glotzer and R. Prekeris (2008) Sequential Cyk4/MgcRacGAP binding to ECT2 and Rab11-FIP3 regulates cleavage furrow ingression and abscission during cytokinesis. EMBO J. 27:1791-1803.

Schonteich, E., G.M, Wilson, J. Burden, C.R. Hopkins, K. Anderson, J.R. Goldenring and R. Prekeris (2008) Rip11/FIP5 and Kinesin II complex regulates endocytic protein recycling. Journal of Cell Science. 121:3824-3833.

Schonteich, E., M. Pilli, G.C. Simon, H.T. Matern, J.R. Junutula, D. Sentz, R.K. Holmes and R. Prekeris (2007) Molecular characterization of Rab11-FIP3 binding to Arf GTPases. European Journal of Cell Biology. 86:417-431.

Yu, X., Prekeris, R., and G. W. Gould (2007) Role of endosomal Rab GTPases in cytokinesis. European Journal for Cell Biology. 86:25-35.

Eathiraj, S., Mishra, A., Prekeris, R., and D.G. Lambright (2006) Structural basis for Rab11-mediated recruitment of FIP3 to recycling endosomes during cytokinesis. Journal of Molecular Biology. 364(2):121-135. ​​