title: γ-Secretase Dependent Nuclear Targeting of Dystroglycan.
abstract: Dystroglycan is frequently lost in adenocarcinoma. α-dystroglycan is known to become hypoglycosylated due to transcriptional silencing of LARGE, whereas β-dystroglycan is proteolytically cleaved and degraded. The mechanism and proteases involved in the cleavage events affecting β-dystroglycan are poorly understood. Using LNCaP prostate cancer cells as a model system, we have investigated proteases and tyrosine phosphorylation affecting β-dystroglycan proteolysis and nuclear targeting. Cell density or phorbol ester treatment increases dystroglycan proteolysis, whereas furin or γ-secretase inhibitors decreased dystroglycan proteolysis. Using resveratrol treatment of LNCaP cells cultured at low cell density in order to up-regulate notch and activate proteolysis, we identified significant increases in the levels of a 26 kDa β-dystroglycan fragment. These data, therefore, support a cell density-dependent γ-secretase and furin mediated proteolysis of β-dystroglycan, which could be notch stimulated, leading to nuclear targeting and subsequent degradation. 117: 2149-2157, 2016. © 2016 The Authors. Journal of Cellular Biochemistry Published by Wiley Periodicals, Inc.
authors.affiliation: Department of Biomedical Science, University of Sheffield, Western Bank, Sheffield S10 2TN, United Kingdom.
authors.forename: Daniel
authors.initials: D
authors.lastname: Leocadio
authors.affiliation: Department of Biomedical Science, University of Sheffield, Western Bank, Sheffield S10 2TN, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Mitchell
authors.affiliation: Department of Biomedical Science, University of Sheffield, Western Bank, Sheffield S10 2TN, United Kingdom.
authors.forename: Steve J
authors.initials: SJ
authors.lastname: Winder
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D049030:Dystroglycans / Q000235:genetics / Q000378:metabolism*; D045683:Furin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D011480:Protease Inhibitors / Q000494:pharmacology; D059748:Proteolysis
chemical_list: D011480:Protease Inhibitors; D049030:Dystroglycans; D053829:Amyloid Precursor Protein Secretases; C468731:FURIN protein, human; D045683:Furin
keywords: DYSTROGLYCAN; PROSTATE CANCER; PROTEOLYSIS