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Item Role of PERK in Anchorage-Independent Growth of Colorectal Carcinoma and Cell Migration In-Vitro(2020-09) Shukla, Madhura Shirish; Wek, Ronald C.; Quilliam, Lawrence A.; Goebl, Mark G.The unfolded protein response (UPR) is important for cell adaptation to accumulation of unfolded proteins in the endoplasmic reticulum (ER). A central UPR sensor of ER stress is PKR- like ER Kinase (PERK), which phosphorylates eIF2 to reduce global translation and help mitigate ER stress. While this is a survival mechanism that serves to save the cell from catastrophic events during ER stress, PERK can also be activated in cancer cells due to genetic changes and exposure to stresses inherent in the tumor micro-environment. Published reports have indicated that PERK is activated in cancer cells in response to hypoxia, nutrient deprivation, matrix detachment, and increased protein load by oncogene activation to facilitate cell survival. The UPR features PERK and another ER stress sensory protein, IRE1α, which also regulates the dynamic assembly of the actin cytoskeleton; loss of either PERK or IRE1α functions decrease cell migration activity. We hypothesized that PERK is required for anchorage-independent survival of the cancer cell line HCT116 and that PERK is essential for cell migration. Consistent with these premises, inhibition of PERK using pharmacological inhibitors GSK2656157 and LY-4 in suspended cells showed reduced growth. Furthermore, PERK-deficient cells showed reduced migration in transwell migration assays as compared to their wild type counterpart. These results suggest that PERK facilitates anchorage-independent growth of cancer cells and cell migration.Item Toxoplasma gondii Co-opts the Unfolded Protein Response To Enhance Migration and Dissemination of Infected Host Cells(American Society for Microbiology, 2020-07-07) Augusto, Leonardo; Martynowicz, Jennifer; Amin, Parth H.; Alakhras, Nada S.; Kaplan, Mark H.; Wek, Ronald C.; Sullivan, William J.; Biochemistry and Molecular Biology, School of MedicineToxoplasma gondii is an intracellular parasite that reconfigures its host cell to promote pathogenesis. One consequence of Toxoplasma parasitism is increased migratory activity of host cells, which facilitates dissemination. Here, we show that Toxoplasma triggers the unfolded protein response (UPR) in host cells through calcium release from the endoplasmic reticulum (ER). We further identify a novel role for the host ER stress sensor protein IRE1 in Toxoplasma pathogenesis. Upon infection, Toxoplasma activates IRE1, engaging its noncanonical role in actin remodeling through the binding of filamin A. By inducing cytoskeletal remodeling via IRE1 oligomerization in host cells, Toxoplasma enhances host cell migration in vitro and dissemination of the parasite to host organs in vivo. Our study has identified novel mechanisms used by Toxoplasma to induce dissemination of infected cells, providing new insights into strategies for treatment of toxoplasmosis.