Professor, Biological Chemistry
M.D., University of Manitoba
Postdoctoral, University of Toronto & New York University
Our laboratory is interested in the role of protein-protein interaction domains in cell biologic processes. We presently study the role of these interaction domains in cell signaling and polarity.
Cell polarity represents a process that allows a cell to have a different protein composition at different membrane surfaces. The ability to develop cell polarity is crucial for many cellular processes including neuronal transmission, cell fate determination, cell migration and epithelial cell function. In epithelia, apical and basolateral surfaces exist that contain different protein components. These surfaces are separated by a seal called the tight junction that separates these two membrane domains. We have been studying a protein called Pals1 (Protein Associated with Lin Seven-1) that localizes to the tight junction of epithelial cells. Pals1 contains numerous protein-protein interaction domains and we have identified a unique domain in Pals1 called the L27 domain that allows Pals1 to target to tight junctions. One of the L27 domains of Pals1 mediates its interaction with another tight junction protein known as Patj (Pals1 Associated Tight Junction Protein). Pals1 also contains a PDZ domain that allows it to interact with the carboxy-terminus of a transmembrane protein called Crumbs. We have found that this protein complex plays a pivotal role in cell polarity and tight junction formation. While our work has demonstrated that this Pals1 complex is important for tight junction assembly and cell polarity, the signaling pathway that allows this complex to control tight junction assembly and cell polarity is unclear. However it has been known that a complex of proteins including a small G protein Cdc42, two PDZ domain proteins, Par3 and Par6 as well as Protein Kinase C isosymes, PKC-zeta and PKC-lambda also exist at the tight junction. We have recently demonstrated that Pals1 can also interact with Par6 connecting these two protein complexes in cells. This suggests that Pals1 is at the center of a signaling complex that can control the formation of tight junctions and direct cell polarity. Further research is focusing on the pathways activated by these proteins that promote tight junction assembly and control the trafficking of proteins to apical versus basolateral surfaces.
1990-1995 Lucille P. Markley Scholar
1992-1995 Kaplan Scholar Award
1997 American Society of Nephrology/American Heart Assoc. Young Investigator Award
2001 Faculty Recognition Award
Roh M.H., Fan S., Liu, C-J. and Margolis, B. The Crumbs3/Pals1 Complex Participates in the Establishment of Polarity in Mammalian Epithelial Cells. J. Cell Sci., 116:2895-906, 2003.
Hurd T.W., Gao, L., Roh, M.H., Macara, I.G., and Margolis, B. Direct interaction of two polarity complexes implicated in epithelial tight junction assembly Nat Cell Biol. 5:137-42, 2003.
Hurd T.W., Fan S., Liu C.J., Kweon H.K., Hakansson K. and Margolis B. Phosphorylation-dependent binding of 14-3-3 to the polarity protein Par3 regulates cell polarity in mammalian epithelia. Curr Biol. 13: 2082-90, 2003.
Fan S., Hurd T.W., Liu C.J., Straight S.W., Weimbs T., Hurd E.A,, Domino S.E. and Margolis B. Polarity proteins control ciliogenesis via kinesin motor interactions. Curr. Biol., 14:1451-61, 2004.
Shin, K, Straight S. and Margolis, B. PATJ Regulates Tight Junction Formation and Polarity in Mammalian Epithelial Cells. J. Cell Biol. 168(5):705-11, 2005.
Straight S.W., Pieczynski J.N., Whiteman E.L., Liu C.J. and Margolis B. Lin-7 stabilizes polarity protein complexes. J Biol Chem. 281:37738-47, 2006. http://www.jbc.org/cgi/content/full/281/49/37738
Wang Q., Chen X.W. and Margolis B. PALS1 Regulates E-Cadherin Trafficking in Mammalian Epithelial Cells. Mol Biol Cell. 18:874-85, 2007. http://www.molbiolcell.org/cgi/content/full/18/3/874
Shin K., Wang Q. and Margolis B.. PATJ Regulates Directional Migration of Mammalian Epithelial Cells. EMBO R, 8:158-64, 2007. http://www.nature.com/embor/journal/v8/n2/abs/7400890.html
Fan S., Fogg V., Wang Q., Chen X.W., Liu C.J. and Margolis B. A novel Crumbs3 isoform regulates cell division and ciliogenesis via importin Î² interactions. J. Cell Biol, 178:387-98, 2007. http://jcb.rupress.org/cgi/content/full/178/3/387
Whiteman E.L., Liu C.J., Fearon E.R. and Margolis B. The transcription factor snail represses Crumbs3 expression and disrupts apico-basal polarity complexes. Oncogene, 27:3875-9, 2008. http://www.nature.com/onc/journal/v27/n27/abs/onc20089a.html