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Proteomic analysis of human T cell-derived exosomes reveals differential RAS/MAPK signaling.

ABSTRACT: Exosomes are cell-derived vesicles that have been implicated in the pathogenesis of many inflammatory diseases. More specifically, it has been shown that T cell-derived exosomes can induce immunological responses; however, little is known about the mechanism and the molecular content of these vesicles. Here, we used a proteomic approach to characterize human T cell-derived exosomes. We found that specific proteins of the RAS signaling pathway were enriched in exosomes derived from activated T cells, and that these vesicles induced ERK phosphorylation in recipient immune cells. Our findings support a mechanistic role of exosomes in cellular activation, and further studies should consider exosomes as a biomarker for inflammatory diseases.

SUBMITTER: Azoulay-Alfaguter I

PROVIDER: S-EPMC6544359 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Proteomic analysis of human T cell-derived exosomes reveals differential RAS/MAPK signaling.

Azoulay-Alfaguter Inbar I Mor Adam A

European journal of immunology 20181003 11

Exosomes are cell-derived vesicles that have been implicated in the pathogenesis of many inflammatory diseases. More specifically, it has been shown that T cell-derived exosomes can induce immunological responses; however, little is known about the mechanism and the molecular content of these vesicles. Here, we used a proteomic approach to characterize human T cell-derived exosomes. We found that specific proteins of the RAS signaling pathway were enriched in exosomes derived from activated T ce ...[more]

PMID: 30207595

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Project description:BackgroundRecent studies have implicated aberrant Notch signaling in breast cancers. Yet, relatively little is known about the pattern of expression of various components of the Notch pathway, or its mechanism of action. To better understand the role of the Notch pathway in breast cancer, we have undertaken a detailed expression analysis of various Notch receptors, their ligands, and downstream targets at different stages of breast cancer progression.ResultsWe report here that there is a general increase in the expression levels of Notch 1, 2, 4, Jagged1, Jagged2, and Delta-like 4 proteins in breast cancers, with simultaneous upregulation of multiple Notch receptors and ligands in a given cancer tissue. While Notch3 and Delta-like1 were undetectable in normal tissues, moderate to high expression was detected in several cancers. We detected the presence of active, cleaved Notch1, along with downstream targets of the Notch pathway, Hes1/Hes5, in approximately 75% of breast cancers, clearly indicating that in a large proportion of breast cancers Notch signaling is aberrantly activated. Furthermore, we detected cleaved Notch1 and Hes1/5 in early precursors of breast cancers - hyperplasia and ductal carcinoma in situ - suggesting that aberrant Notch activation may be an early event in breast cancer progression. Mechanistically, while constitutively active Notch1 alone failed to transform immortalized breast cells, it synergized with the Ras/MAPK pathway to mediate transformation. This cooperation is reflected in vivo, as a subset of cleaved Notch positive tumors additionally expressed phopsho-Erk1/2 in the nuclei. Such cases exhibited high node positivity, suggesting that Notch-Ras cooperation may lead to poor prognosis.ConclusionsHigh level expression of Notch receptors and ligands, and its increased activation in several breast cancers and early precursors, places Notch signaling as a key player in breast cancer pathogenesis. Its cooperation with the Ras/MAPK pathway in transformation offers combined inhibition of the two pathways as a new modality for breast cancer treatment.

Dataset Information

Proteomic analysis of human T cell-derived exosomes reveals differential RAS/MAPK signaling.

Publications

Proteomic analysis of human T cell-derived exosomes reveals differential RAS/MAPK signaling.

Similar Datasets

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