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

Am J Pathol. 2012 Dec;181(6):2172-87. doi: 10.1016/j.ajpath.2012.08.025. Epub 2012 Sep 29.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology*
  • Caveolin 1 / metabolism
  • Cell Compartmentation / drug effects
  • Cell Line, Tumor
  • Cell Movement* / drug effects
  • Cytoskeletal Proteins / metabolism*
  • Female
  • Gene Knockdown Techniques
  • Humans
  • Hyaluronan Receptors / metabolism*
  • Hyaluronic Acid / pharmacology
  • Membrane Microdomains / metabolism*
  • Membrane Proteins / metabolism
  • Models, Biological
  • Protein Binding / drug effects
  • Protein Transport / drug effects
  • Subcellular Fractions / metabolism
  • beta-Cyclodextrins / pharmacology


  • Caveolin 1
  • Cytoskeletal Proteins
  • Hyaluronan Receptors
  • Membrane Proteins
  • beta-Cyclodextrins
  • ezrin
  • flotillins
  • Hyaluronic Acid
  • betadex