Browsing by Subject "Fucosylation"

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    NF-κB Signaling Is Regulated by Fucosylation in Metastatic Breast Cancer Cells
    (MDPI, 2020-12-12) Doud, Emma H.; Shetty, Trupti; Abt, Melissa; Mosley, Amber L.; Corson, Timothy W.; Mehta, Anand; Yeh, Elizabeth S.; Biochemistry and Molecular Biology, School of Medicine
    A growing body of evidence indicates that the levels of fucosylation correlate with breast cancer progression and contribute to metastatic disease. However, very little is known about the signaling and functional outcomes that are driven by fucosylation. We performed a global proteomic analysis of 4T1 metastatic mammary tumor cells in the presence and absence of a fucosylation inhibitor, 2-fluorofucose (2FF). Of significant interest, pathway analysis based on our results revealed a reduction in the NF-κB and TNF signaling pathways, which regulate the inflammatory response. NF-κB is a transcription factor that is pro-tumorigenic and a prime target in human cancer. We validated our results, confirming that treatment of 4T1 cells with 2FF led to a decrease in NF-κB activity through increased IκBα. Based on these observations, we conclude that fucosylation is an important post-translational modification that governs breast cancer cell signaling.
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    Pathogenic Variants in Fucokinase Cause a Congenital Disorder of Glycosylation
    (Elsevier, 2018-12-06) Ng, Bobby G.; Rosenfeld, Jill A.; Emrick, Lisa; Jain, Mahim; Burrage, Lindsay C.; Lee, Brendan; Craigen, William J.; Bearden, David R.; Graham, Brett H.; Freeze, Hudson H.; Medical and Molecular Genetics, School of Medicine
    FUK encodes fucokinase, the only enzyme capable of converting L-fucose to fucose-1-phosphate, which will ultimately be used for synthesizing GDP-fucose, the donor substrate for all fucosyltransferases. Although it is essential for fucose salvage, this pathway is thought to make only a minor contribution to the total amount of GDP-fucose. A second pathway, the major de novo pathway, involves conversion of GDP-mannose to GDP-fucose. Here we describe two unrelated individuals who have pathogenic variants in FUK and who presented with severe developmental delays, encephalopathy, intractable seizures, and hypotonia. The first individual was compound heterozygous for c.667T>C (p.Ser223Pro) and c.2047C>T (p.Arg683Cys), and the second individual was homozygous for c.2980A>C (p.Lys994Gln). Skin fibroblasts from the first individual confirmed the variants as loss of function and showed significant decreases in total GDP-[3H] fucose and [3H] fucose-1-phosphate. There was also a decrease in the incorporation of [5,6-3H]-fucose into fucosylated glycoproteins. Lys994 has previously been shown to be an important site for ubiquitin conjugation. Here, we show that loss-of-function variants in FUK cause a congenital glycosylation disorder characterized by a defective fucose-salvage pathway.