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

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posted on 22.11.2019 by Simona Donatello, Irina S. Babina, Lee D. Hazelwood, Arnold DK Hill, Ivan R. Nabi, Ann M. Hopkins

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.

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This article is also available at http://www.sciencedirect.com/science/article/pii/S0002944012006670 or http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3502863/

Published Citation

Donatello S, Babina IS, Hazelwood LD, Hill AD, Nabi IR, Hopkins AM. Lipid Raft association restricts CD44-ezrin interaction and promotion of breast cancer cell migration. American Journal of Pathology. 2012;181(6):2172-87.

Publication Date

01/12/2012

Publisher

American Society for Investigative Pathology

PubMed ID

23031255

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