期刊
CELL CYCLE
卷 12, 期 21, 页码 3421-3432出版社
LANDES BIOSCIENCE
DOI: 10.4161/cc.26431
关键词
EGFR; Interleukin 6; Interleukin 6 receptor; SASP; mTOR; senescence
类别
资金
- DFG grant [SCHE 907/2-1]
- Collaborative Research Center [SFB 728]
- DFG
- Research Commission of the Medical Faculty of the Heinrich-Heine-University
- DFG [SFB877]
- Cluster of Excellence Inflammation at Interfaces
- Alexander von Humboldt Foundation(SKA)
- German Research Foundation
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.
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