title: Lipid raft association restricts CD44-ezrin interaction and promotion of breast cancer cell migration.
abstract: Cancer cell migration is an early event in metastasis, the main cause of breast cancer-related deaths. Cholesterol-enriched membrane domains called lipid rafts influence the function of many molecules, including the raft-associated protein CD44. We describe a novel mechanism whereby rafts regulate interactions between CD44 and its binding partner ezrin in migrating breast cancer cells. Specifically, in nonmigrating cells, CD44 and ezrin localized to different membranous compartments: CD44 predominantly in rafts, and ezrin in nonraft compartments. After the induction of migration (either nonspecific or CD44-driven), CD44 affiliation with lipid rafts was decreased. This was accompanied by increased coprecipitation of CD44 and active (threonine-phosphorylated) ezrin-radixin-moesin (ERM) proteins in nonraft compartments and increased colocalization of CD44 with the nonraft protein, transferrin receptor. Pharmacological raft disruption using methyl-β-cyclodextrin also increased CD44-ezrin coprecipitation and colocalization, further suggesting that CD44 interacts with ezrin outside rafts during migration. Conversely, promoting CD44 retention inside lipid rafts by pharmacological inhibition of depalmitoylation virtually abolished CD44-ezrin interactions. However, transient single or double knockdown of flotillin-1 or caveolin-1 was not sufficient to increase cell migration over a short time course, suggesting complex crosstalk mechanisms. We propose a new model for CD44-dependent breast cancer cell migration, where CD44 must relocalize outside lipid rafts to drive cell migration. This could have implications for rafts as pharmacological targets to down-regulate cancer cell migration.
authors.affiliation: Department of Surgery, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland.
authors.forename: Simona
authors.initials: S
authors.lastname: Donatello
authors.forename: Irina S
authors.initials: IS
authors.lastname: Babina
authors.forename: Lee D
authors.initials: LD
authors.lastname: Hazelwood
authors.forename: Arnold D K
authors.initials: AD
authors.lastname: Hill
authors.forename: Ivan R
authors.initials: IR
authors.lastname: Nabi
authors.forename: Ann M
authors.initials: AM
authors.lastname: Hopkins
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D051242:Caveolin 1 / Q000378:metabolism; D002451:Cell Compartmentation / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000494:pharmacology; D021962:Membrane Microdomains / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D008954:Models, Biological; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D013347:Subcellular Fractions / Q000378:metabolism; D047392:beta-Cyclodextrins / Q000494:pharmacology; D000099149:Ezrin
chemical_list: D051242:Caveolin 1; D003598:Cytoskeletal Proteins; D018960:Hyaluronan Receptors; D006820:Hyaluronic Acid; D008565:Membrane Proteins; D047392:beta-Cyclodextrins; D000099149:Ezrin; C106354:flotillins; C031215:betadex