title: Cellular senescence or EGFR signaling induces Interleukin 6 (IL-6) receptor expression controlled by mammalian target of rapamycin (mTOR).
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.
authors.affiliation: Institute of Biochemistry and Molecular Biology II; Medical Faculty; Heinrich-Heine-University; Düsseldorf, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Garbers
authors.forename: Fabian
authors.initials: F
authors.lastname: Kuck
authors.forename: Samadhi
authors.initials: S
authors.lastname: Aparicio-Siegmund
authors.forename: Kirstin
authors.initials: K
authors.lastname: Konzak
authors.forename: Mareike
authors.initials: M
authors.lastname: Kessenbrock
authors.forename: Annika
authors.initials: A
authors.lastname: Sommerfeld
authors.forename: Dieter
authors.initials: D
authors.lastname: Häussinger
authors.forename: Philipp A
authors.initials: PA
authors.lastname: Lang
authors.forename: Dirk
authors.initials: D
authors.lastname: Brenner
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.forename: Frank
authors.initials: F
authors.lastname: Essmann
authors.forename: Klaus
authors.initials: K
authors.lastname: Schulze-Osthoff
authors.forename: Roland P
authors.initials: RP
authors.lastname: Piekorz
authors.forename: Jürgen
authors.initials: J
authors.lastname: Scheller
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016922:Cellular Senescence / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D005326:Fetal Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D005326:Fetal Proteins; D015850:Interleukin-6; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; D019947:Receptors, Interleukin-6; C418485:TACC3 protein, mouse; C546843:mTOR protein, mouse; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse
keywords: EGFR; Interleukin 6; Interleukin 6-Receptor; SASP; mTOR; senescence
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