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Research Article Summary BIOL 501-Senior Project Author, Title, Journal, Year, Volume, Pages Eboni Stafford Tuomi, S., Mai, A., Nevo, J., Laine, J., Vilkki, V., Ohman, T., Gahmberg, C., Parker, P., Ivaska, J. (2009). PKC ε Regulation of an α5 Integrin-ZO-1 Complex Controls Lamellae Formation in Migrating Cancer Cells . Cell Biology. Volume 2. 77. Key Terms Introduction/ Purpose Integrin, ZO-1, migrating cells Research Methods Question/Hypothesis During carcinogenesis, epithelia cells lose their characteristic epithelial feature and become increasingly motile and invasive. Reduced ZO-1, a tight junction protein, has been reported to correlate w/increased invasiveness. Loss of ZO-1 from intercellular adhesions, increased α5β1 integrin, and activation of PKCε have been shown to correlate /increased invasion and poor prognosis in lung cancer. They want to show that a spatially restricted α5 integrinZO-1 interaction, which is dynamically regulated by PKCε, triggers They want to show that a spatially restricted α5 integrin- ZO-1 interaction, which is dynamically regulated by PKCε, triggers persistent migration in lung cancer cells. Cell culture: NCIH460 non-small cell lung cancer cells, immunofluorescenc e, DNA constructs and transfection, PKC kinase assay, gene silencing and rescue, immunohistochemis try, ELISA, migration assays and cell proliferation analysis, adhesion assays, inverted 3-D invasion assay, Rac activation assay, Integrin internalization assay, Flow cytometry, statistical analysis Results Conclusion/Discussion -ZO-1 and α5 regulate lamelle formation and migration -α5β1 integrin and ZO-1 association is spatially restricted to lamellae -ZO-1 interacts directly w/a noncanonical PDZ binding motif unique to the α5 integrin cytoplasmic tail. -The α5-ZO-1 complex is present in lung cancer clinical samples -PKCε regulates the formation of the α5-ZO1 complex -Phosphorylation regulates ZO-1 subcellular localization Conclusion: PKCε Regulation of an α5 Integrn-ZO- 1 complex controls lamellae formation in migrating cancer cells Discussion: Transition from normal cells to invasive cancer cells involves disassembly of cell-cell adhesions and remodeling of the actin cytoskeleton and integrincontaining adhesion sites. The migration switch is controlled by PKCε which regulates ZO-1 phosphorylation on Ser 168. ZO-1 PDZ domains appear to have a dual role in cells. The PKCε-regulated localization of the α integrin-ZO-1 complex to the leading edge is a molecular migration switch w/a potentially critical role in cancer cell invasion. Research Article Summary BIOL 501-Senior Project persistent migration in lung cancer cells. Eboni Stafford