Abstract
Interleukin 6 (IL-6) signaling plays a role in inflammation, cancer, and senescence. Here, we identified soluble IL-6 receptor (sIL-6R) as a member of the senescence-associated secretory phenotype (SASP). Senescence-associated sIL-6R upregulation was mediated by mammalian target of rapamycin (mTOR). sIL-6R was mainly generated by a disintegrin and metalloprotease 10 (ADAM10)-dependent ectodomain shedding to enable IL-6 trans-signaling. In vivo, heterozygous PTEN-knockout mice exhibited higher mTOR activity and increased sIL-6R levels. Moreover, aberrant EGF receptor (EGFR) activation triggered IL-6 synthesis. In analogy to senescence, EGFR-induced activation of mTOR also induced IL-6R expression and sIL-6R generation. Hence, mTOR activation reprograms IL-6 non-responder cells into IL-6 responder cells. Our data suggest that mTOR serves as a central molecular switch to facilitate cellular IL-6 classic and trans-signaling via IL-6R upregulation with direct implications for cellular senescence and tumor development.
Keywords:
EGFR; Interleukin 6; Interleukin 6-Receptor; SASP; mTOR; senescence.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ADAM Proteins / genetics
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ADAM Proteins / metabolism
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ADAM10 Protein
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Amyloid Precursor Protein Secretases / genetics
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Amyloid Precursor Protein Secretases / metabolism
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Animals
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Carrier Proteins / antagonists & inhibitors
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Cell Line
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Cell Transformation, Neoplastic / genetics*
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Cell Transformation, Neoplastic / metabolism
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Cell Transformation, Neoplastic / pathology
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Cellular Senescence / genetics
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ErbB Receptors / genetics*
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ErbB Receptors / metabolism
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Fetal Proteins / antagonists & inhibitors
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Fetal Proteins / genetics
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Fetal Proteins / metabolism
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Gene Expression Regulation, Neoplastic*
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Humans
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Interleukin-6 / genetics*
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Interleukin-6 / metabolism
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice
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Mice, Knockout
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Microtubule-Associated Proteins / antagonists & inhibitors
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / metabolism
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PTEN Phosphohydrolase / deficiency
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PTEN Phosphohydrolase / genetics
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Receptors, Interleukin-6 / genetics*
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Receptors, Interleukin-6 / metabolism
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Signal Transduction
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TOR Serine-Threonine Kinases / genetics*
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TOR Serine-Threonine Kinases / metabolism
Substances
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Carrier Proteins
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Fetal Proteins
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Interleukin-6
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Membrane Proteins
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Microtubule-Associated Proteins
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RNA, Small Interfering
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Receptors, Interleukin-6
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TACC3 protein, mouse
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mTOR protein, mouse
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EGFR protein, mouse
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ErbB Receptors
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TOR Serine-Threonine Kinases
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PTEN Phosphohydrolase
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PTEN protein, human
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Amyloid Precursor Protein Secretases
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ADAM Proteins
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ADAM10 Protein
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Adam10 protein, mouse