Concerted functions of Gab1 and Shp2 in liver regeneration and hepatoprotection
Concerted functions of Gab1 and Shp2 in liver regeneration and hepatoprotection
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DOI：
10.1128/mcb.02253-05
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发表时间：
2006-06-01
影响因子：
5.3
通讯作者：
Feng, Gen-Sheng
中科院分区：
文献类型：
--
作者：
Bard-Chapeau, Emilie A.;Yuan, Jing;Feng, Gen-Sheng
肝再生是对损伤的快速和协调的反应，其中生长因子产生的细胞内信号导致转录因子的激活、DNA合成和肝细胞增殖。然而，细胞质信号之间的联系导致肝损伤的增殖反应仍有待阐明。我们在这里表明，协会的Gab 1衔接蛋白和Shp 2酪氨酸磷酸酶是一个关键的事件，在早期阶段的肝再生。部分肝切除术（PH）快速和短暂地诱导组装的复合物，包括Shp 2和酪氨酸磷酸化的Gab 1在野生型肝细胞。一致的是，肝脏特异性Shp 2基因敲除（LSKO）和肝脏特异性Gab 1基因敲除（LGKO）小鼠显示出非常相似的PH引发的肝再生缺陷表型，包括钝化的细胞外信号调节激酶1/2（Erk 1/2）激活，立即早期基因表达减少，细胞周期蛋白A，E和B1水平降低，以及肝细胞增殖抑制。相比之下，Akt和白细胞介素-6/Stat3途径在LSKO和LGKO小鼠中在切除术后上调，伴随着肝脏保护的改善。总的来说，这项研究建立了生理意义的Gab 1/Shp 2链接在促进有丝分裂信号通过Erk途径在哺乳动物肝再生。
Liver regeneration is a rapid and concerted response to injury, in which growth factor-generated intracellular signals result in activation of transcription factors, DNA synthesis, and hepatocyte proliferation. However, the link between cytoplasmic signals resulting in proliferative response to liver injury remains to be elucidated. We show here that association of Gab1 adaptor protein and Shp2 tyrosine phosphatase is a critical event at the early phase of liver regeneration. Partial hepatectomy (PH) rapidly and transiently induced assembly of a complex comprising Shp2 and tyrosine-phosphorylated Gab1 in wild-type hepatocytes. Consistently, liver-specific Shp2 knockout (LSKO) and liver-specific Gab1 knockout (LGKO) mice displayed very similar phenotypes of defective liver regeneration triggered by PH, including blunted extracellular signal-regulated kinase 1/2 (Erk1/2) activation, decreased expression of immediate-early genes, and reduced levels of cyclins A, E, and B1, as well as suppression of hepatocyte proliferation. In contrast, the Akt and interleukin-6/Stat3 pathways were up-regulated posthepatectomy in LSKO and LGKO mice, accompanied by improved hepatoprotection. Collectively, this study establishes the physiological significance of the Gab1/Shp2 link in promoting mitogenic signaling through the Erk pathway in mammalian liver regeneration.