Lipid raft association restricts CD44-ezrin interaction and promotion of breast cancer cell migration.

Hdl Handle:
http://hdl.handle.net/10147/292693
Title:
Lipid raft association restricts CD44-ezrin interaction and promotion of breast cancer cell migration.
Authors:
Donatello, Simona; Babina, Irina S; Hazelwood, Lee D; Hill, Arnold D K; Nabi, Ivan R; Hopkins, Ann M
Affiliation:
Department of Surgery, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland.
Citation:
Lipid raft association restricts CD44-ezrin interaction and promotion of breast cancer cell migration. 2012, 181 (6):2172-87 Am. J. Pathol.
Journal:
The American journal of pathology
Issue Date:
Dec-2012
URI:
http://hdl.handle.net/10147/292693
DOI:
10.1016/j.ajpath.2012.08.025
PubMed ID:
23031255
Additional Links:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3502863/
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.
Item Type:
Article
Language:
en
MeSH:
Antigens, CD44; Breast Neoplasms; Caveolin 1; Cell Compartmentation; Cell Line, Tumor; Cell Movement; Cytoskeletal Proteins; Female; Gene Knockdown Techniques; Humans; Hyaluronic Acid; Membrane Microdomains; Membrane Proteins; Models, Biological; Protein Binding; Protein Transport; Subcellular Fractions; beta-Cyclodextrins
ISSN:
1525-2191

Full metadata record

DC FieldValue Language
dc.contributor.authorDonatello, Simonaen_GB
dc.contributor.authorBabina, Irina Sen_GB
dc.contributor.authorHazelwood, Lee Den_GB
dc.contributor.authorHill, Arnold D Ken_GB
dc.contributor.authorNabi, Ivan Ren_GB
dc.contributor.authorHopkins, Ann Men_GB
dc.date.accessioned2013-05-24T09:06:04Z-
dc.date.available2013-05-24T09:06:04Z-
dc.date.issued2012-12-
dc.identifier.citationLipid raft association restricts CD44-ezrin interaction and promotion of breast cancer cell migration. 2012, 181 (6):2172-87 Am. J. Pathol.en_GB
dc.identifier.issn1525-2191-
dc.identifier.pmid23031255-
dc.identifier.doi10.1016/j.ajpath.2012.08.025-
dc.identifier.urihttp://hdl.handle.net/10147/292693-
dc.description.abstractCancer 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.en_GB
dc.description.urihttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3502863/-
dc.language.isoenen
dc.relation.urlhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3502863/en_GB
dc.rightsArchived with thanks to The American journal of pathologyen_GB
dc.subject.meshAntigens, CD44-
dc.subject.meshBreast Neoplasms-
dc.subject.meshCaveolin 1-
dc.subject.meshCell Compartmentation-
dc.subject.meshCell Line, Tumor-
dc.subject.meshCell Movement-
dc.subject.meshCytoskeletal Proteins-
dc.subject.meshFemale-
dc.subject.meshGene Knockdown Techniques-
dc.subject.meshHumans-
dc.subject.meshHyaluronic Acid-
dc.subject.meshMembrane Microdomains-
dc.subject.meshMembrane Proteins-
dc.subject.meshModels, Biological-
dc.subject.meshProtein Binding-
dc.subject.meshProtein Transport-
dc.subject.meshSubcellular Fractions-
dc.subject.meshbeta-Cyclodextrins-
dc.titleLipid raft association restricts CD44-ezrin interaction and promotion of breast cancer cell migration.en_GB
dc.typeArticleen
dc.contributor.departmentDepartment of Surgery, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland.en_GB
dc.identifier.journalThe American journal of pathologyen_GB
dc.description.provinceLeinsteren

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