EGFR stimulation enables IL-6 trans-signalling via
iRhom2-dependent ADAM17 activation in mammary epithelial cells

J 2023

EGFR stimulation enables IL-6 trans-signalling via iRhom2-dependent ADAM17 activation in mammary epithelial cells

SCHUMACHER, Neele, Ilka THOMSEN, Florian BRUNDERT, Václav HEJRET, Stefan DUESTERHOFT et. al.

Základní údaje

Originální název

EGFR stimulation enables IL-6 trans-signalling via iRhom2-dependent ADAM17 activation in mammary epithelial cells

Autoři

SCHUMACHER, Neele, Ilka THOMSEN, Florian BRUNDERT, Václav HEJRET (203 Česká republika, domácí), Stefan DUESTERHOFT, Boris TICHÝ (203 Česká republika, domácí), Dirk SCHMIDT-ARRAS, Matthias VOSS a Stefan ROSE-JOHN

Vydání

Biochimica et biophysica acta : Molecular Cell Research, Amsterdam, Elsevier, 2023, 0167-4889

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10608 Biochemistry and molecular biology

Stát vydavatele

Nizozemské království

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 5.100 v roce 2022

Kód RIV

RIV/00216224:14740/23:00133609

Organizační jednotka

Středoevropský technologický institut

DOI

http://dx.doi.org/10.1016/j.bbamcr.2023.119489

UT WoS

001057807300001

Klíčová slova anglicky

Interleukin-6; IL-6 trans -signalling; EGFR; ADAM17; iRhom2

Štítky

CF BIOIT, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 31. 10. 2024 12:14, Ing. Marie Švancarová

Anotace

V originále

The cytokine interleukin-6 (IL-6) has considerable pro-inflammatory properties and is a driver of many physiological and pathophysiological processes. Cellular responses to IL-6 are mediated by membrane-bound or soluble forms of the IL-6 receptor (IL-6R) complexed with the signal-transducing subunit gp130. While expression of the membrane-bound IL-6R is restricted to selected cell types, soluble IL-6R (sIL-6R) enables gp130 engagement on all cells, a process termed IL-6 trans-signalling and considered to be pro-inflammatory. sIL-6R is predominantly generated through proteolytic processing by the metalloproteinase ADAM17. ADAM17 also liberates ligands of the epidermal growth factor receptor (EGFR), which is a prerequisite for EGFR activation and results in stimulation of proliferative signals. Hyperactivation of EGFR mostly due to activating mutations drives cancer development. Here, we reveal an important link between overshooting EGFR signalling and the IL-6 trans-signalling pathway. In epithelial cells, EGFR activity induces not only IL-6 expression but also the proteolytic release of sIL-6R from the cell membrane by increasing ADAM17 surface activity. We find that this derives from the transcriptional upregulation of iRhom2, a crucial regulator of ADAM17 trafficking and activation, upon EGFR engagement, which results in increased surface localization of ADAM17. Also, phosphorylation of the EGFRdownstream mediator ERK mediates ADAM17 activity via interaction with iRhom2. In sum, our study reveals an unforeseen interplay between EGFR activation and IL-6 trans-signalling, which has been shown to be fundamental in inflammation and cancer.

Návaznosti

LX22NPO5104, projekt VaV

Název: Národní institut pro výzkum metabolických a kardiovaskulárních onemocnění (Akronym: CarDia)

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, Národní institut pro léčbu metabolických a kardiovaskulárních onemocnění, 5.1 EXCELES

90267, velká výzkumná infrastruktura

Název: NCMG III

Citovat

SCHUMACHER, Neele, Ilka THOMSEN, Florian BRUNDERT, Václav HEJRET, Stefan DUESTERHOFT, Boris TICHÝ, Dirk SCHMIDT-ARRAS, Matthias VOSS a Stefan ROSE-JOHN. EGFR stimulation enables IL-6 trans-signalling via iRhom2-dependent ADAM17 activation in mammary epithelial cells. Biochimica et biophysica acta : Molecular Cell Research. Amsterdam: Elsevier, 2023, roč. 1870, č. 7, s. 1-16. ISSN 0167-4889. Dostupné z: https://dx.doi.org/10.1016/j.bbamcr.2023.119489.

@article{2376917,
   author = {Schumacher, Neele and Thomsen, Ilka and Brundert, Florian and Hejret, Václav and Duesterhoft, Stefan and Tichý, Boris and SchmidtandArras, Dirk and Voss, Matthias and RoseandJohn, Stefan},
   article_location = {Amsterdam},
   article_number = {7},
   doi = {http://dx.doi.org/10.1016/j.bbamcr.2023.119489},
   keywords = {Interleukin-6; IL-6 trans -signalling; EGFR; ADAM17; iRhom2},
   language = {eng},
   issn = {0167-4889},
   journal = {Biochimica et biophysica acta : Molecular Cell Research},
   title = {EGFR stimulation enables IL-6 trans-signalling via iRhom2-dependent ADAM17 activation in mammary epithelial cells},
   url = {https://www.sciencedirect.com/science/article/pii/S0167488923000617?via%3Dihub},
   volume = {1870},
   year = {2023}
}

TY  - JOUR
ID  - 2376917
AU  - Schumacher, Neele - Thomsen, Ilka - Brundert, Florian - Hejret, Václav - Duesterhoft, Stefan - Tichý, Boris - Schmidt-Arras, Dirk - Voss, Matthias - Rose-John, Stefan
PY  - 2023
TI  - EGFR stimulation enables IL-6 trans-signalling via iRhom2-dependent ADAM17 activation in mammary epithelial cells
JF  - Biochimica et biophysica acta : Molecular Cell Research
VL  - 1870
IS  - 7
SP  - 1-16
EP  - 1-16
PB  - Elsevier
SN  - 01674889
KW  - Interleukin-6
KW  - IL-6 trans -signalling
KW  - EGFR
KW  - ADAM17
KW  - iRhom2
UR  - https://www.sciencedirect.com/science/article/pii/S0167488923000617?via%3Dihub
N2  - The cytokine interleukin-6 (IL-6) has considerable pro-inflammatory properties and is a driver of many physiological and pathophysiological processes. Cellular responses to IL-6 are mediated by membrane-bound or soluble forms of the IL-6 receptor (IL-6R) complexed with the signal-transducing subunit gp130. While expression of the membrane-bound IL-6R is restricted to selected cell types, soluble IL-6R (sIL-6R) enables gp130 engagement on all cells, a process termed IL-6 trans-signalling and considered to be pro-inflammatory. sIL-6R is predominantly generated through proteolytic processing by the metalloproteinase ADAM17. ADAM17 also liberates ligands of the epidermal growth factor receptor (EGFR), which is a prerequisite for EGFR activation and results in stimulation of proliferative signals. Hyperactivation of EGFR mostly due to activating mutations drives cancer development. Here, we reveal an important link between overshooting EGFR signalling and the IL-6 trans-signalling pathway. In epithelial cells, EGFR activity induces not only IL-6 expression but also the proteolytic release of sIL-6R from the cell membrane by increasing ADAM17 surface activity. We find that this derives from the transcriptional upregulation of iRhom2, a crucial regulator of ADAM17 trafficking and activation, upon EGFR engagement, which results in increased surface localization of ADAM17. Also, phosphorylation of the EGFRdownstream mediator ERK mediates ADAM17 activity via interaction with iRhom2. In sum, our study reveals an unforeseen interplay between EGFR activation and IL-6 trans-signalling, which has been shown to be fundamental in inflammation and cancer.
ER  -

SCHUMACHER, Neele, Ilka THOMSEN, Florian BRUNDERT, Václav HEJRET, Stefan DUESTERHOFT, Boris TICHÝ, Dirk SCHMIDT-ARRAS, Matthias VOSS a Stefan ROSE-JOHN. EGFR stimulation enables IL-6 trans-signalling via iRhom2-dependent ADAM17 activation in mammary epithelial cells. \textit{Biochimica et biophysica acta : Molecular Cell Research}. Amsterdam: Elsevier, 2023, roč.~1870, č.~7, s.~1-16. ISSN~0167-4889. Dostupné z: https://dx.doi.org/10.1016/j.bbamcr.2023.119489.

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