title: Ezrin regulates focal adhesion and invadopodia dynamics by altering calpain activity to promote breast cancer cell invasion.
abstract: Up-regulation of the cytoskeleton linker protein ezrin frequently occurs in aggressive cancer types and is closely linked with metastatic progression. However, the underlying molecular mechanisms detailing how ezrin is involved in the invasive and metastatic phenotype remain unclear. Here we report a novel function of ezrin in regulating focal adhesion (FA) and invadopodia dynamics, two key processes required for efficient invasion to occur. We show that depletion of ezrin expression in invasive breast cancer cells impairs both FA and invadopodia turnover. We also demonstrate that ezrin-depleted cells display reduced calpain-mediated cleavage of the FA and invadopodia-associated proteins talin, focal adhesion kinase (FAK), and cortactin and reduced calpain-1-specific membrane localization, suggesting a requirement for ezrin in maintaining proper localization and activity of calpain-1. Furthermore, we show that ezrin is required for cell directionality, early lung seeding, and distant organ colonization but not primary tumor growth. Collectively our results unveil a novel mechanism by which ezrin regulates breast cancer cell invasion and metastasis.
authors.affiliation: Division of Cancer Biology and Genetics, Cancer Research Institute, Queen's University, Kingston, ON K7L 3N6, Canada Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON K7L 3N6, Canada.
authors.forename: Victoria
authors.initials: V
authors.lastname: Hoskin
authors.affiliation: Division of Cancer Biology and Genetics, Cancer Research Institute, Queen's University, Kingston, ON K7L 3N6, Canada Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON K7L 3N6, Canada.
authors.forename: Alvin
authors.initials: A
authors.lastname: Szeto
authors.affiliation: Division of Cancer Biology and Genetics, Cancer Research Institute, Queen's University, Kingston, ON K7L 3N6, Canada Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON K7L 3N6, Canada.
authors.forename: Abdi
authors.initials: A
authors.lastname: Ghaffari
authors.affiliation: Division of Cancer Biology and Genetics, Cancer Research Institute, Queen's University, Kingston, ON K7L 3N6, Canada Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON K7L 3N6, Canada.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Greer
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L 3N6, Canada.
authors.forename: Graham P
authors.initials: GP
authors.lastname: Côté
authors.affiliation: Division of Cancer Biology and Genetics, Cancer Research Institute, Queen's University, Kingston, ON K7L 3N6, Canada Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON K7L 3N6, Canada elliottb@queensu.ca.
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Elliott
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D002154:Calpain / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism*; D003599:Cytoskeleton / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D022001:Focal Adhesions / Q000378:metabolism*; D057809:HEK293 Cells; D064593:Heterografts; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis; D000069261:Podosomes / Q000378:metabolism*; D016608:Talin / Q000378:metabolism; D000099149:Ezrin
chemical_list: D002154:Calpain; D003598:Cytoskeletal Proteins; D051416:Focal Adhesion Protein-Tyrosine Kinases; D016608:Talin; D000099149:Ezrin