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.

Basic information

Original name

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

Authors

SCHUMACHER, Neele, Ilka THOMSEN, Florian BRUNDERT, Václav HEJRET (203 Czech Republic, belonging to the institution), Stefan DUESTERHOFT, Boris TICHÝ (203 Czech Republic, belonging to the institution), Dirk SCHMIDT-ARRAS, Matthias VOSS and Stefan ROSE-JOHN

Edition

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

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10608 Biochemistry and molecular biology

Country of publisher

Netherlands

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 5.100 in 2022

RIV identification code

RIV/00216224:14740/23:00133609

Organization unit

Central European Institute of Technology

DOI

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

UT WoS

001057807300001

Keywords in English

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

Abstract

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.

Links

LX22NPO5104, research and development project

Name: Národní institut pro výzkum metabolických a kardiovaskulárních onemocnění (Acronym: CarDia)

Investor: Ministry of Education, Youth and Sports of the CR, 5.1 EXCELES

90267, large research infrastructures

Name: NCMG III

Citovat

SCHUMACHER, Neele, Ilka THOMSEN, Florian BRUNDERT, Václav HEJRET, Stefan DUESTERHOFT, Boris TICHÝ, Dirk SCHMIDT-ARRAS, Matthias VOSS and 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, vol. 1870, No 7, p. 1-16. ISSN 0167-4889. Available from: 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 and 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, vol.~1870, No~7, p.~1-16. ISSN~0167-4889. Available from: https://dx.doi.org/10.1016/j.bbamcr.2023.119489.

Detailed Information on Publication Record