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.

A role for dystroglycan in the pathophysiology of acute leukemic cells

“…Thus, we hypothesize that proteolysis of the -Dg ectodomain [38] or of -Dg's N-terminal portion [39][40][41] produced by Matrix MetalloProteinases (MMP) Furin andsecretase [42], respectively, may contribute to the pathophysiology of the AML, as these have been implicated in cancer progression in other systems [43,44]. Recently, it was established that hypoglycosylation severely alters -Dg's capability to bind to ECM partners, facilitating its degradation by MMP-2 or by other enzymes not identified to date [45]; additionally, in some patients affected by dystroglycanopathy, an important reduction of the Dg core protein was identified [46].…”

Nintedanib treatment delays prostate dorsolateral lobe cancer progression in the TRAMP model: contribution to the epithelial‐stromal interaction balance

“…but also in the post-transductional levels (Sgambato et al, 2007). Also, studies suggested that there were possible posttranscriptional mechanisms, such as proteolitic enzymes which could modulate the DG expression as well as its link with the basal lamina in cancer (Bao et al, 2009;Leocadio et al, 2016).…”

Profiling of the muscle-specific dystroglycan interactome reveals the role of Hippo signaling in muscular dystrophy and age-dependent muscle atrophy

“…Studies in mammalian system suggest that proteolysis, tyrosine phosphorylation, and translocation of Dg to the nucleus result in altered gene transcription [110]. A recent study in prostate cancer cells showed cell densitydependent γ-secretase and furin-mediated proteolysis of β-dystroglycan which could be stimulated by Notch, leading to nuclear targeting [111]. Another work uncovered the mechanism of retrograde trafficking of βdystroglycan from the plasma membrane to the nucleus [112].…”