Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 181, Issue 6, Pages 2172-2187Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2012.08.025
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Funding
- Cancer Research Ireland [CRI05HOP/AMH]
- Irish Research Council for Science, Engineering Technology [EMBARK 2005/SD]
- Health Research Board of Ireland [HRA/2009/49]
- Breast Cancer Ireland
- Network of Excellence ENFIN [LSHG-CT2005-518254]
- UK Medical Research Council
- National Biophotonics and Imaging Platform, Ireland
- Irish Government's Programme for Research in Third Level Institutions, Cycle 4, Ireland's EU Structural Funds Programmes
- Health Research Board (HRB) [HRA-2009-49] Funding Source: Health Research Board (HRB)
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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-beta-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. (Am J Pathol 2012, 181:2172-2187; http://dx.doi.org/10.1016/j.ajpath.2012.08.025)
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