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Quantitative Measurement of γ-Secretase-mediated Amyloid Precursor Protein and Notch Cleavage in Cell-based Luciferase Reporter Assay Platforms
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γ-Secretase Dependent Nuclear Targeting of Dystroglycan

Daniel Leocadio1, Andrew Mitchell1, Steve J Winder1

  • 1Department of Biomedical Science, University of Sheffield, Western Bank, Sheffield S10 2TN, United Kingdom.

Journal of Cellular Biochemistry
|March 19, 2016
PubMed

Insights

Beta-dystroglycan proteolysis is increased by cell density and Notch signaling, involving furin and gamma-secretase. This process leads to beta-dystroglycan nuclear targeting and degradation in prostate cancer cells.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Cancer Research

Background:

  • Dystroglycan, a key component of the cell membrane, is often lost in adenocarcinoma.
  • While alpha-dystroglycan hypoglycosylation is linked to LARGE gene silencing, the proteases and mechanisms behind beta-dystroglycan cleavage are unclear.

Purpose of the Study:

  • To investigate the proteases and tyrosine phosphorylation involved in beta-dystroglycan proteolysis and nuclear targeting.
  • To elucidate the role of cell density and signaling pathways in beta-dystroglycan degradation using LNCaP prostate cancer cells.

Main Methods:

  • Utilized LNCaP prostate cancer cells as a model system.
  • Investigated the effects of cell density, phorbol ester, resveratrol, and specific protease inhibitors (furin, gamma-secretase) on beta-dystroglycan.
  • Analyzed beta-dystroglycan fragments and nuclear localization.

Main Results:

  • Increased cell density and phorbol ester treatment enhanced beta-dystroglycan proteolysis.
  • Furin and gamma-secretase inhibitors reduced beta-dystroglycan proteolysis.
  • Resveratrol treatment at low cell density, coupled with Notch pathway activation, significantly increased a 26 kDa beta-dystroglycan fragment.

Conclusions:

  • Beta-dystroglycan proteolysis is mediated by furin and gamma-secretase in a cell density-dependent manner.
  • Notch signaling may stimulate this proteolysis, leading to beta-dystroglycan nuclear targeting and degradation.
  • These findings provide insights into the mechanisms of dystroglycan loss in cancer.
Keywords:
DYSTROGLYCANPROSTATE CANCERPROTEOLYSIS

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