Met provides essential signals for liver regeneration
Met provides essential signals for liver regeneration
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DOI：
10.1073/pnas.0403412101
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发表时间：
2004-07-20
影响因子：
11.1
通讯作者：
Birchmeier, C
中科院分区：
文献类型：
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作者：
Borowiak, M;Garratt, AN;Birchmeier, C
对小鼠的遗传分析表明，Met酪氨酸激酶受体及其配体肝细胞生长因子/分散因子(HGF/SF)在肝脏、肌肉和胎盘的发育中起着至关重要的作用。在这里，我们使用小鼠的条件突变来分析Met在肝脏再生过程中的功能，使用Mx-cre转基因在成人中引入突变。在携带Mx-cre-Met突变的小鼠进行部分肝切除后，肝脏的再生受到损害。对照和突变肝脏中信号转导通路的比较表明，Met和其他信号受体合作，完全激活特定的信号分子，例如蛋白激酶Akt。然而，肝再生过程中ERK1/2激酶的激活完全依赖于Met。因此，信号串扰是肝脏再生调节的一个重要方面。对条件Met突变小鼠肝细胞周期进程的分析表明，Met突变小鼠有缺陷地退出静止期，进入S期的次数减少。肝再生受损伴随着代偿性生理反应，包括外周血中HGF/SF和IL-6的长期上调。我们的数据表明，HGF/SF/Met信号系统不仅在肝脏发育过程中是必不可少的，而且对成人器官的再生也是必不可少的。
Genetic analysis in mice has demonstrated a crucial role of the Met tyrosine kinase receptor and its ligand, hepatocyte growth factor/scatter factor (HGF/SF), in development of the liver, muscle, and placenta. Here, we use conditional mutagenesis in mice to analyze the function of Met during liver regeneration, using the Mx-cre transgene to introduce the mutation in the adult. After partial hepatectomy in mice carrying the Mx-cre-incluced Met mutation, regeneration of the liver is impaired. Comparison of signal transduction pathways in control and mutant livers indicates that Met and other signaling receptors cooperate to fully activate particular signaling molecules, for instance, the protein kinase Akt. However, activation of the Erk1/2 kinase during liver regeneration depends exclusively on Met. Signaling crosstalk is thus an important aspect of the regulation of liver regeneration. Analysis of cell cycle progression of hepatocytes in conditional Met mutant mice indicates a defective exit from quiescence and diminished entry into S phase. Impaired liver regeneration is accompanied by compensatory physiological responses that include prolonged up-regulation of HGF/SF and IL-6 in peripheral blood. Our data demonstrate that the HGF/SF/Met signaling system is essential not only during liver development but also for the regeneration of the organ in the adult.