Smad proteins and hepatocyte growth factor control parallel regulatory pathways that converge on β1-integrin to promote normal liver development
Smad proteins and hepatocyte growth factor control parallel regulatory pathways that converge on β1-integrin to promote normal liver development
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DOI：
10.1128/mcb.21.15.5122-5131.2001
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发表时间：
2001-08-01
影响因子：
5.3
通讯作者：
Deng, CX
中科院分区：
文献类型：
--
作者：
Einstein, M;Monga, SPS;Deng, CX
Smads充当转化生长因子β（TGF-β）信号传导的细胞内介质。在被活化的I型TGF-β受体磷酸化后，Smad蛋白易位到细胞核，在那里它们充当转录因子并增加或减少TGF-β靶基因的表达。由于肝脏发育不全和贫血，缺少Smad 2和Smad 3各一个拷贝的小鼠遭受妊娠中期致死，这表明TGF-β信号组分的必需剂量要求。这可能是由于突变肝细胞的异常粘附特性，这可能是由于β 1-整联蛋白水平降低和E-钙粘蛋白的异常加工和定位所致。体外培养的突变体肝脏显示存在一个平行的发育途径介导的肝细胞生长因子（HGF），这可以拯救突变体的表型不依赖于Smad激活。这些途径在β 1-整合素处合并，在培养的突变肝脏中，HGF增加了β 1-整合素的水平。HGF处理逆转了Smad 2（+/-）; Smad 3（+/-）肝脏中细胞增殖和肝脏结构的缺陷。
Smads serve as intracellular mediators of transforming growth factor beta (TGF-beta) signaling. After phosphorylation by activated type I TGF-beta receptors, Smad proteins translocate to the nucleus, where they serve as transcription factors and increase or decrease expression of TGF-beta target genes, Mice lacking one copy each of Smad2 and Smad3 suffered midgestation lethality due to liver hypoplasia and anemia, suggesting essential dosage requirements of TGF-beta signal components. This is likely due to abnormal adhesive properties of the mutant hepatocytes, which may result from a decrease in the level of the beta1-integrin and abnormal processing and localization of E-cadherin. Culture of mutant livers in vitro revealed the existence of a parallel developmental pathway mediated by hepatocyte growth factor (HGF), which could rescue the mutant phenotype independent of Smad activation. These pathways merge at the beta1-integrin, the level of which was increased by HGF in the cultured mutant livers. HGF treatment reversed the defects in cell proliferation and hepatic architecture in the Smad2(+/-); Smad3(+/-) livers.