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- Title
An extracellular vesicular mutant KRAS‐associated protein complex promotes lung inflammation and tumor growth.
- Authors
Sriwastva, Mukesh K.; Teng, Yun; Mu, Jingyao; Xu, Fangyi; Kumar, Anil; Sundaram, Kumaran; Malhotra, Rajiv Kumar; Xu, Qingbo; Hood, Joshua L.; Zhang, Lifeng; Yan, Jun; Merchant, Michael L.; Park, Juw Won; Dryden, Gerald W.; Egilmez, Nejat K.; Zhang, Huang‐Ge
- Abstract
Extracellular vesicles (EVs) contain more than 100 proteins. Whether there are EVs proteins that act as an 'organiser' of protein networks to generate a new or different biological effect from that identified in EV‐producing cells has never been demonstrated. Here, as a proof‐of‐concept, we demonstrate that EV‐G12D‐mutant KRAS serves as a leader that forms a protein complex and promotes lung inflammation and tumour growth via the Fn1/IL‐17A/FGF21 axis. Mechanistically, in contrast to cytosol derived G12D‐mutant KRAS complex from EVs‐producing cells, EV‐G12D‐mutant KRAS interacts with a group of extracellular vesicular factors via fibronectin‐1 (Fn1), which drives the activation of the IL‐17A/FGF21 inflammation pathway in EV recipient cells. We show that: (i), depletion of EV‐Fn1 leads to a reduction of a number of inflammatory cytokines including IL‐17A; (ii) induction of IL‐17A promotes lung inflammation, which in turn leads to IL‐17A mediated induction of FGF21 in the lung; and (iii) EV‐G12D‐mutant KRAS complex mediated lung inflammation is abrogated in IL‐17 receptor KO mice. These findings establish a new concept in EV function with potential implications for novel therapeutic interventions in EV‐mediated disease processes.
- Subjects
MUTANT proteins; PNEUMONIA; TUMOR growth; LUNG tumors; LUNGS; EXTRACELLULAR vesicles; BIOLOGICAL networks
- Publication
Journal of Extracellular Vesicles, 2023, Vol 12, Issue 2, p1
- ISSN
2001-3078
- Publication type
Article
- DOI
10.1002/jev2.12307