ADAM10/17-dependent release of soluble c-Met correlates with hepatocellular damage.
ADAM10/17-dependent release of soluble c-Met correlates with hepatocellular damage.
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发表时间：
2013
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影响因子：
0.6
通讯作者：
K. Chalupský;I. Kanchev;O. Zbodakova;H. Buryová;M. Jiroušková;V. Kořínek;M. Gregor;R. Sedláček
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作者：
K. Chalupský;I. Kanchev;O. Zbodakova;H. Buryová;M. Jiroušková;V. Kořínek;M. Gregor;R. Sedláček
肝细胞生长因子(HGF)及其受体c-Met激活的信号通路是肝脏发育和再生不可缺少的信号通路。已经描述了c-Met是通过去整合素和金属蛋白酶10(ADAM10)从细胞表面释放出来的，从而产生一种可溶的c-Met形式，称为Smet。利用人肝细胞株HepG2和肝星状细胞Lx2，我们发现ADAM17和ADAM10都能从肝细胞表面释放Smet，其中ADAM17似乎是主要的蛋白水解酶。此外，在3，5-二乙氧甲酰-1，4-二羟基氯(DDC)诱导的肝胆梗阻小鼠模型上，我们发现血清Smet水平与肝脏损伤状态和连续再生以及已建立的肝损伤标志物如丙氨酸氨基转移酶(ALT)、天冬氨酸转氨酶(AST)、碱性磷酸酶(ALP)和总胆红素有很好的相关性。然而，与血清肿瘤坏死因子α(肿瘤坏死因子α)相比，SMET与肝脏损伤和炎症的相关性明显更好，后者的脱落也是由ADAM蛋白分解活性介导的。我们的结果表明，ADAM10/17的蛋白分解活性对于调节HGF/c-Met信号在急性肝损伤和随后的再生中是必不可少的，血清中不同水平的Smet和c-Met/HGF的表达可能不仅是损伤的有用指标，而且可能是正在进行的肝再生的指标。
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.