Endocytic trafficking of laminin is controlled by dystroglycan and is disrupted in cancers

Dmitri Leonoudakis, Ge Huang, Armin Akhavan, Jimmie E. Fata, Manisha Singh, Joe Gray, John Muschler

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

The dynamic interactions between cells and basement membranes serve as essential regulators of tissue architecture and function in metazoans, and perturbation of these interactions contributes to the progression of a wide range of human diseases, including cancers. Here, we reveal the pathway and mechanism for the endocytic trafficking of a prominent basement membrane protein, laminin-111 (referred to here as laminin), and their disruption in disease. Livecell imaging of epithelial cells revealed pronounced internalization of laminin into endocytic vesicles. Laminin internalization was receptor mediated and dynamin dependent, and laminin proceeded to the lysosome through the late endosome. Manipulation of laminin receptor expression revealed that the dominant regulator of laminin internalization is dystroglycan, a laminin receptor that is functionally perturbed in muscular dystrophies and in many cancers. Correspondingly, laminin internalization was found to be deficient in aggressive cancer cells displaying non-functional dystroglycan, and restoration of dystroglycan function strongly enhanced the endocytosis of laminin in both breast cancer and glioblastoma cells. These results establish previously unrecognized mechanisms for the modulation of cell-basement-membrane communication in normal cells and identify a profound disruption of endocytic laminin trafficking in aggressive cancer subtypes.

Original languageEnglish (US)
Pages (from-to)4894-4903
Number of pages10
JournalJournal of Cell Science
Volume127
Issue number22
DOIs
StatePublished - 2014

Fingerprint

Dystroglycans
Laminin
Neoplasms
Basement Membrane
Laminin Receptors
Cell Membrane
Dynamins
Transport Vesicles
Muscular Dystrophies
Endosomes
Glioblastoma
Endocytosis
Lysosomes
Membrane Proteins
Epithelial Cells
Communication
Breast Neoplasms

Keywords

  • Cancer
  • Dystroglycan
  • Endocytosis
  • Laminin

ASJC Scopus subject areas

  • Cell Biology
  • Medicine(all)

Cite this

Endocytic trafficking of laminin is controlled by dystroglycan and is disrupted in cancers. / Leonoudakis, Dmitri; Huang, Ge; Akhavan, Armin; Fata, Jimmie E.; Singh, Manisha; Gray, Joe; Muschler, John.

In: Journal of Cell Science, Vol. 127, No. 22, 2014, p. 4894-4903.

Research output: Contribution to journalArticle

Leonoudakis, Dmitri ; Huang, Ge ; Akhavan, Armin ; Fata, Jimmie E. ; Singh, Manisha ; Gray, Joe ; Muschler, John. / Endocytic trafficking of laminin is controlled by dystroglycan and is disrupted in cancers. In: Journal of Cell Science. 2014 ; Vol. 127, No. 22. pp. 4894-4903.
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