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Presenter: Paola Cruz Graduate Student, Department of Chemistry and Biochemistry
Abstract: TGF-β activated kinase (TAK1) is a major activator of alpha-tublin-N-acetyltransferas (αTAT1), a major microtubule acetyltranferase. TAK1 has been shown to directly interact with αTAT1 to enhance its catalytic activity at Ser237. These findings have suggested a novel role of TGF-β signaling in microtubule related functions and disease.
One major focus of our work has been on TAK1/αTAT1-based ER remodeling and its rle in inhibiting apoptosis by downregulating BOK, a major ER membrane-associated proapoptotic effector. BOK is rapidly degraded due to its dissociation from IP3R during ER conversion from perinuclear sheets to tubules, a finding that is reversed upon targeted inhibition of the TAK1/αTAT1 pathway. These findings suggest a distinct mechanism of MT-based ER remodeling and cell survival in response to cellular cues.
To further study the role of αTAT1 in disease, specifically phosphorylation of Ser237, we conducted a screening assay using different cancer cell lines, which allowed the identification of pancreatic cancer as having some of the most upregulation of αTAT1-pS237 compared to other cancers. In vitro and in vivo assays have been conducted suggesting lower cell proliferation for the αTAT1-S237A mutants as seen by an in vitro cell proliferation assay, as well as by an in vivo xenograft mouse model conducted over 60 days, where mice were injected with PANC1 WT and αTAT1-pS237 cells. Harvested tumors for the WT showed an increase in size. Quantitative proteomics was used as a tool to identify target proteins associated with the difference in proliferation when comparing WT and αTAT1-S237A lysates. We further identified NDRG4, a known tumor suppressor, whose function have previously been linked to cell proliferation and cell viability. Our data suggest αTAT1-S237 as a possible therapeutic target in pancreatic cancer.