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Exosome Uptake Depends on ERK1/2-Heat Shock Protein 27 Signaling and Lipid Raft-mediated Endocytosis Negatively Regulated by Caveolin-1
- Source :
- The Journal of Biological Chemistry
- Publication Year :
- 2013
- Publisher :
- Elsevier BV, 2013.
-
Abstract
- Background: Exosome vesicles can transfer molecular information previously shown to stimulate tumor development; however, the mechanism of exosome uptake is unknown. Results: Mammalian cells internalize exosomes through lipid raft-mediated endocytosis negatively regulated by caveolin-1. Conclusion: Our findings provide novel insights into cellular uptake of exosomes. Significance: Our data provide potential strategies for how the exosome uptake pathway may be targeted.<br />The role of exosomes in cancer can be inferred from the observation that they transfer tumor cell derived genetic material and signaling proteins, resulting in e.g. increased tumor angiogenesis and metastasis. However, the membrane transport mechanisms and the signaling events involved in the uptake of these virus-like particles remain ill-defined. We now report that internalization of exosomes derived from glioblastoma (GBM) cells involves nonclassical, lipid raft-dependent endocytosis. Importantly, we show that the lipid raft-associated protein caveolin-1 (CAV1), in analogy with its previously described role in virus uptake, negatively regulates the uptake of exosomes. We find that exosomes induce the phosphorylation of several downstream targets known to associate with lipid rafts as signaling and sorting platforms, such as extracellular signal-regulated kinase-1/2 (ERK1/2) and heat shock protein 27 (HSP27). Interestingly, exosome uptake appears dependent on unperturbed ERK1/2-HSP27 signaling, and ERK1/2 phosphorylation is under negative influence by CAV1 during internalization of exosomes. These findings significantly advance our general understanding of exosome-mediated uptake and offer potential strategies for how this pathway may be targeted through modulation of CAV1 expression and ERK1/2 signaling.
- Subjects :
- Caveolin
MAP Kinase Signaling System
Endosome
media_common.quotation_subject
Caveolin 1
HSP27 Heat-Shock Proteins
CHO Cells
Endosomes
Biology
Exosomes
Endocytosis
Biochemistry
Exosome
Mice
Membrane Microdomains
Cricetinae
Chlorocebus aethiops
Nitriles
Butadienes
Human Umbilical Vein Endothelial Cells
Animals
Humans
Vesicles
Phosphorylation
Extracellular Signal-Regulated MAP Kinases
Internalization
Molecular Biology
Lipid raft
Cells, Cultured
Cytoskeleton
Heat-Shock Proteins
media_common
Biological Transport
Cell Biology
Membrane transport
Microvesicles
Cell biology
COS Cells
Glioblastoma
Protein Processing, Post-Translational
HeLa Cells
Molecular Chaperones
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 288
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....1a2a231f4450785169c8b9161029f71b