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.