Proteolytic enzymes and altered glycosylation modulate dystroglycan function in carcinoma cells

Jarnail Singh, Yoko Itahana, Selena Knight-Krajewski, Motoi Kanagawa, Kevin P. Campbell, Mina J. Bissell, John Muschler

Research output: Contribution to journalArticle

83 Scopus citations

Abstract

Alterations in the basement membrane receptor dystroglycan (DG) are evident in muscular dystrophies and carcinoma cells and characterized by a selective loss or modification of the extracellular α-DG subunit. Defects in posttranslational modifications of DG have been identified in some muscular dystrophies, but the underlying modifications in carcinoma cells have not yet been defined. We reveal here multiple posttranslational modifications that modulate the composition and function of DG in normal epithelial cells and carcinoma cells. We show that α-DG is shed from the cell surface of normal and tumorigenic epithelial cells through a proteolytic mechanism that does not require direct cleavage of either α- or β-DG. Shedding is dependent on metalloprotease activity and the proprotein convertase furin. Surprisingly, furin is also found to directly process α-DG as a proprotein substrate, changing the existing model of DG composition. We also show that the glycosylation of α-DG is altered in invasive carcinoma cells, and this modification causes complete loss of laminin binding properties. Together, these data elucidate several novel events regulating the functional composition of DG and reveal defects that arise during cancer progression, providing direction for efforts to restore this link with the basement membrane in carcinoma cells.

Original languageEnglish (US)
Pages (from-to)6152-6159
Number of pages8
JournalCancer Research
Volume64
Issue number17
DOIs
StatePublished - Sep 1 2004

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Singh, J., Itahana, Y., Knight-Krajewski, S., Kanagawa, M., Campbell, K. P., Bissell, M. J., & Muschler, J. (2004). Proteolytic enzymes and altered glycosylation modulate dystroglycan function in carcinoma cells. Cancer Research, 64(17), 6152-6159. https://doi.org/10.1158/0008-5472.CAN-04-1638