ADAM10 and ADAM17 regulate EGFR, c-Met and TNF RI signalling in liver regeneration and fibrosis

Abstract ADAM10 and ADAM17 are proteases that affect multiple signalling pathways by releasing molecules from the cell surface. As their substrate specificities partially overlaps, we investigated their concurrent role in liver regeneration and fibrosis, using three liver-specific deficient mouse li...

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Autores principales:	Olga Zbodakova, Karel Chalupsky, Lenka Sarnova, Petr Kasparek, Marketa Jirouskova, Martin Gregor, Radislav Sedlacek
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/df2cddcbdde34b69ae1e9c24d053e8ad
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spelling	oai:doaj.org-article:df2cddcbdde34b69ae1e9c24d053e8ad2021-12-02T17:51:21ZADAM10 and ADAM17 regulate EGFR, c-Met and TNF RI signalling in liver regeneration and fibrosis10.1038/s41598-021-90716-32045-2322https://doaj.org/article/df2cddcbdde34b69ae1e9c24d053e8ad2021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-90716-3https://doaj.org/toc/2045-2322Abstract ADAM10 and ADAM17 are proteases that affect multiple signalling pathways by releasing molecules from the cell surface. As their substrate specificities partially overlaps, we investigated their concurrent role in liver regeneration and fibrosis, using three liver-specific deficient mouse lines: ADAM10- and ADAM17-deficient lines, and a line deficient for both proteases. In the model of partial hepatectomy, double deficient mice exhibited decreased AKT phosphorylation, decreased release of EGFR activating factors and lower shedding of HGF receptor c-Met. Thus, simultaneous ablation of ADAM10 and ADAM17 resulted in inhibited EGFR signalling, while HGF/c-Met signalling pathway was enhanced. In contrast, antagonistic effects of ADAM10 and ADAM17 were observed in the model of chronic CCl4 intoxication. While ADAM10-deficient mice develop more severe fibrosis manifested by high ALT, AST, ALP and higher collagen deposition, combined deficiency of ADAM10 and ADAM17 surprisingly results in comparable degree of liver damage as in control littermates. Therefore, ADAM17 deficiency is not protective in fibrosis development per se, but can ameliorate the damaging effect of ADAM10 deficiency on liver fibrosis development. Furthermore, we show that while ablation of ADAM17 resulted in decreased shedding of TNF RI, ADAM10 deficiency leads to increased levels of soluble TNF RI in serum. In conclusion, hepatocyte-derived ADAM10 and ADAM17 are important regulators of growth receptor signalling and TNF RI release, and pathological roles of these proteases are dependent on the cellular context.Olga ZbodakovaKarel ChalupskyLenka SarnovaPetr KasparekMarketa JirouskovaMartin GregorRadislav SedlacekNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Olga Zbodakova Karel Chalupsky Lenka Sarnova Petr Kasparek Marketa Jirouskova Martin Gregor Radislav Sedlacek ADAM10 and ADAM17 regulate EGFR, c-Met and TNF RI signalling in liver regeneration and fibrosis
description	Abstract ADAM10 and ADAM17 are proteases that affect multiple signalling pathways by releasing molecules from the cell surface. As their substrate specificities partially overlaps, we investigated their concurrent role in liver regeneration and fibrosis, using three liver-specific deficient mouse lines: ADAM10- and ADAM17-deficient lines, and a line deficient for both proteases. In the model of partial hepatectomy, double deficient mice exhibited decreased AKT phosphorylation, decreased release of EGFR activating factors and lower shedding of HGF receptor c-Met. Thus, simultaneous ablation of ADAM10 and ADAM17 resulted in inhibited EGFR signalling, while HGF/c-Met signalling pathway was enhanced. In contrast, antagonistic effects of ADAM10 and ADAM17 were observed in the model of chronic CCl4 intoxication. While ADAM10-deficient mice develop more severe fibrosis manifested by high ALT, AST, ALP and higher collagen deposition, combined deficiency of ADAM10 and ADAM17 surprisingly results in comparable degree of liver damage as in control littermates. Therefore, ADAM17 deficiency is not protective in fibrosis development per se, but can ameliorate the damaging effect of ADAM10 deficiency on liver fibrosis development. Furthermore, we show that while ablation of ADAM17 resulted in decreased shedding of TNF RI, ADAM10 deficiency leads to increased levels of soluble TNF RI in serum. In conclusion, hepatocyte-derived ADAM10 and ADAM17 are important regulators of growth receptor signalling and TNF RI release, and pathological roles of these proteases are dependent on the cellular context.
format	article
author	Olga Zbodakova Karel Chalupsky Lenka Sarnova Petr Kasparek Marketa Jirouskova Martin Gregor Radislav Sedlacek
author_facet	Olga Zbodakova Karel Chalupsky Lenka Sarnova Petr Kasparek Marketa Jirouskova Martin Gregor Radislav Sedlacek
author_sort	Olga Zbodakova
title	ADAM10 and ADAM17 regulate EGFR, c-Met and TNF RI signalling in liver regeneration and fibrosis
title_short	ADAM10 and ADAM17 regulate EGFR, c-Met and TNF RI signalling in liver regeneration and fibrosis
title_full	ADAM10 and ADAM17 regulate EGFR, c-Met and TNF RI signalling in liver regeneration and fibrosis
title_fullStr	ADAM10 and ADAM17 regulate EGFR, c-Met and TNF RI signalling in liver regeneration and fibrosis
title_full_unstemmed	ADAM10 and ADAM17 regulate EGFR, c-Met and TNF RI signalling in liver regeneration and fibrosis
title_sort	adam10 and adam17 regulate egfr, c-met and tnf ri signalling in liver regeneration and fibrosis
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/df2cddcbdde34b69ae1e9c24d053e8ad
work_keys_str_mv	AT olgazbodakova adam10andadam17regulateegfrcmetandtnfrisignallinginliverregenerationandfibrosis AT karelchalupsky adam10andadam17regulateegfrcmetandtnfrisignallinginliverregenerationandfibrosis AT lenkasarnova adam10andadam17regulateegfrcmetandtnfrisignallinginliverregenerationandfibrosis AT petrkasparek adam10andadam17regulateegfrcmetandtnfrisignallinginliverregenerationandfibrosis AT marketajirouskova adam10andadam17regulateegfrcmetandtnfrisignallinginliverregenerationandfibrosis AT martingregor adam10andadam17regulateegfrcmetandtnfrisignallinginliverregenerationandfibrosis AT radislavsedlacek adam10andadam17regulateegfrcmetandtnfrisignallinginliverregenerationandfibrosis
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ADAM10 and ADAM17 regulate EGFR, c-Met and TNF RI signalling in liver regeneration and fibrosis

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