Nuclear translocation of β-dystroglycan reveals a distinctive trafficking pattern of autoproteolyzed mucins

Maria Luisa Oppizzi, Armin Akhavan, Manisha Singh, Jimmie E. Fata, John L. Muschler

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Dystroglycan (DG) is an extracellular matrix receptor implicated in muscular dystrophies and cancers. DG belongs to the membrane-tethered mucin family and is composed of extracellular (α-DG) and transmembrane (β-DG) subunits stably coupled at the cell surface. These two subunits are generated by autoproteolysis of a monomeric precursor within a distinctive protein motif called sea urchin-enterokinase-agrin (SEA) domain, yet the purpose of this cleavage and heterodimer creation is uncertain. In this study, we identify a functional nuclear localization signal within β-DG and show that, in addition to associating with α-DG at the cell surface, the full-length and glycosylated β-DG autonomously traffics to the cytoplasm and nucleoplasm in a process that occurs independent of α-DG ligand binding. The trafficking pattern of β-DG mirrors that of MUC1-C, the transmembrane subunit of the related MUC1 oncoprotein, also a heterodimeric membrane-tethered mucin created by SEA autoproteolysis. We show that the transmembrane subunits of both MUC1 and DG transit the secretory pathway prior to nuclear targeting and that their monomeric precursors maintain the capacity for nuclear trafficking. A screen of breast carcinoma cell lines of distinct pathophysiological origins revealed considerable variability in the nuclear partitioning of β-DG, indicating that nuclear localization of β-DG is regulated, albeit independent of extracellular ligand binding. These findings point to novel intracellular functions for β-DG, with possible disease implications. They also reveal an evolutionarily conserved role for SEA autoproteolysis, serving to enable independent functions of mucin transmembrane subunits, enacted by a shared and poorly understood pathway of segregated subunit trafficking.

Original languageEnglish (US)
Pages (from-to)2063-2072
Number of pages10
JournalTraffic
Volume9
Issue number12
DOIs
StatePublished - Nov 20 2008

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Keywords

  • Dystroglycan
  • MUC1
  • Mucin
  • SEA

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Cell Biology

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