ADAM10/17-Dependent Release of Soluble c-Met Correlates with Hepatocellular Damage

Chalupský, K.; Kanchev, I.; Žbodáková, O.; Buryová, H.; Jiroušková, M.; Kořínek, V.; Gregor, M.; Sedláček, Radislav

doi:10.14712/fb2013059020076

Folia Biologica > Archive > 2013, Vol. 59 > Issue 2 > ADAM10/17-Dependent Release of Soluble…

Fol. Biol. 2013, 59, 76-86

https://doi.org/10.14712/fb2013059020076

ADAM10/17-Dependent Release of Soluble c-Met Correlates with Hepatocellular Damage

K. Chalupský¹, I. Kanchev¹, O. Žbodáková¹, H. Buryová¹, M. Jiroušková¹, V. Kořínek², M. Gregor¹, Radislav Sedláček¹

¹Laboratory of Transgenic Models of Diseases, Institute of Molecular Genetics of the ASCR, v. v. i., Prague, Czech Republic
²Laboratory of Cell and Developmental Biology, Institute of Molecular Genetics of the ASCR, v. v. i., Prague, Czech Republic

Received February 2013
Accepted February 2013

The signalling pathway elicited by hepatocyte growth factor (HGF) and its receptor c-Met is indispensable for liver development and regeneration. It has been described that c-Met is released from the cell surface by a disintegrin and metalloprotease 10 (ADAM10) resulting in a soluble c-Met form known as sMet. Using the human hepatocellular HepG2 and hepatic stellate cell LX2 lines we show that sMet is released from the cell surface of liver cells by both ADAM17 and ADAM10, with ADAM17 appearing to be the major proteinase. Moreover, using a mouse model of 3,5-diethoxycarbonyl-1,4-dihydroxycollidine (DDC)-induced hepatobiliary obstruction we show that serum levels of sMet correlate well with the liver damage state and consecutive regeneration as well as with established markers of liver damage such as alanine aminotransferase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), and total bilirubin. However, sMet exhibited remarkably better correlation with liver damage and inflammation than did serum tumour necrosis factor α (TNF-α), whose shedding is also mediated by ADAM proteolytic activity. Our results indicate that the proteolytic activity of ADAM10/17 is essential for regulating HGF/c-Met signalling during acute liver damage and following regeneration and that the differential serum levels of sMet together with expression of c-Met/HGF might be a useful indicator not only for damage, but also for ongoing liver regeneration.

Keywords

c-Met, HGF, shedding, ADAM metalloproteinase, liver, cholangitis.

Funding

Financial support was given to Radislav Sedláček by GACR (P305/10/2143), GACR (P303/10/2044), GAAV (IAA500520812), Academy of Sciences of the Czech Republic (RVO 68378050).