title: Endocytic trafficking of laminin is controlled by dystroglycan and is disrupted in cancers.
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. Live-cell 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.
authors.affiliation: California Pacific Medical Center Research Institute, 475 Brannan St., Suite 220, San Francisco, CA 94107, USA.
authors.forename: Dmitri
authors.initials: D
authors.lastname: Leonoudakis
authors.affiliation: Biomedical Engineering Department, Oregon Health and Sciences University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
authors.forename: Ge
authors.initials: G
authors.lastname: Huang
authors.affiliation: California Pacific Medical Center Research Institute, 475 Brannan St., Suite 220, San Francisco, CA 94107, USA.
authors.forename: Armin
authors.initials: A
authors.lastname: Akhavan
authors.affiliation: Department of Biology, College of Staten Island, City University of New York, 2800 Victory Blvd, Staten Island, NY 10314, USA.
authors.forename: Jimmie E
authors.initials: JE
authors.lastname: Fata
authors.affiliation: California Pacific Medical Center Research Institute, 475 Brannan St., Suite 220, San Francisco, CA 94107, USA.
authors.forename: Manisha
authors.initials: M
authors.lastname: Singh
authors.affiliation: Biomedical Engineering Department, Oregon Health and Sciences University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA Center for Spatial Systems Biomedicine, and Knight Cancer Institute, Oregon Health and Sciences University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
authors.forename: Joe W
authors.initials: JW
authors.lastname: Gray
authors.affiliation: California Pacific Medical Center Research Institute, 475 Brannan St., Suite 220, San Francisco, CA 94107, USA Biomedical Engineering Department, Oregon Health and Sciences University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA muschler@ohsu.edu.
authors.forename: John L
authors.initials: JL
authors.lastname: Muschler
mesh_terms: D000818:Animals; D001485:Basement Membrane / Q000378:metabolism; D049030:Dystroglycans / Q000378:metabolism*; D004705:Endocytosis; D005260:Female; D006801:Humans; D007797:Laminin / Q000378:metabolism*; D008321:Mammary Glands, Animal / Q000166:cytology / Q000378:metabolism; D042361:Mammary Glands, Human / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000378:metabolism*; D011247:Pregnancy
chemical_list: D007797:Laminin; D049030:Dystroglycans
keywords: Cancer; Dystroglycan; Endocytosis; Laminin