The signal pthway and the role of the discoidin domain receptor 2 (DDR2) which is stimulated by type I collagen

I型胶原刺激的盘状结构域受体2（DDR2）的信号通路和作用

• 批准号: 14570022
• 负责人: IKEDA Kazuo
• 金额: $ 1.86万
• 依托单位: Osaka City University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570022/
• 关键词: DDR2; collagen; stellate cells; liver fibrosis; Src; Shc; MMP-2

Discoidin domain receptor 2 (DDR2) is an unusual receptor tyrosine kinase in that its ligand is fibrillar collagen rather than a growth factor-like peptide. We tested the signal pathway and the role of DDR2. DDR2 mRNA and protein were induced in hepatic stellate cells activated by primary culture or in vivo during liver injury. The receptor became tyrosine phosphotylated in response to type I collagen. The signaling of DDR2 increased expression of active matrix metalloproteinase 2. We also showed that DDR2 is unusual in that it requires Src activity to be maximally tyrosine phosphorylated, and that Src activity also promotes association of DDR2 with adaptor protein Shc. The interaction with Shc involves a portion of Shc not previously implicated in interaction with receptor tyrosine kinases. These results identify Src kinase and the adaptor protein Shc as key signaling intermediates in DDR2 signal transudction. To further investigate the relation between Src kinase and DDR2 in fibrotic liver, dominant negative Src expressing adeno vector, which expression was regulated by collagen 1A2 promoter, were injected in Thioacetoamide treated rats. Overexpression of dominant negative Src inhibited the phosphoiylation of DDR2 and reduced the histological fibrotic change. The data support a model in which Src and the DDR2 receptor cooperate in a regulated fashion to direct the phosphrylation of both the receptor and its targets.

盘状蛋白结构域受体2（DDR2）是一种不寻常的受体酪氨酸激酶，因为其配体是原纤维胶原蛋白而不是生长因子样肽。我们测试了信号途径和DDR2的作用。 DDR2 mRNA和蛋白质在肝损伤过程中被原发性培养物或体内激活的肝星状细胞诱导。该受体因I型胶原蛋白而变成酪氨酸磷酸化。 DDR2的信号增加了活性基质金属蛋白酶2的表达。我们还表明DDR2是不寻常的，因为它要求SRC活性是最大的酪氨酸磷酸化的，并且SRC活性还促进了DDR2与衔接蛋白SHC的关联。与SHC的相互作用涉及以前与受体酪氨酸激酶相互作用的一部分SHC。这些结果将SRC激酶和衔接蛋白SHC鉴定为DDR2信号渗透中的关键信号中间体。为了进一步研究纤维化肝脏中SRC激酶与DDR2之间的关系，在硫代酰胺治疗的大鼠中注入了胶原蛋白1A2启动子的表达的显性负SRC，表达adeno载体（表达受胶原蛋白1A2启动子）的调节。显性阴性SRC的过表达抑制了DDR2的磷酸化，并减少了组织学纤维化变化。数据支持一个模型，在该模型中，SRC和DDR2受体以受调节的方式合作，以指导受体及其靶标的磷酸化。

项目成果

Uyama N, Shimahara Y, Okuyama H, Kawada N, Kamo S, Ikeda K, Yamaoka Y.: "Carbenoxolone inhibits DNA synthesis and collagen gene expression in rat hepatic stellate cells in culture"J Hepatol. 39(5). 749-755 (2003)

Uyama N、Shimahara Y、Okuyama H、Kawada N、Kamo S、Ikeda K、Yamaoka Y.：“Carbenoxolone 抑制培养物中大鼠肝星状细胞的 DNA 合成和胶原蛋白基因表达”J Hepatol。

Uyama N. et al.: "Carbenoxolone inhibits DNA synthesis and collagen gene expression in rat hepatic stellate cells in culture."J Hepatol.. 39・5. 749-755 (2003)

Uyama N. 等人：“Carbenoxolone 抑制培养的大鼠肝星状细胞中的 DNA 合成和胶原蛋白基因表达。”J Hepatol.. 749-755 (2003)。

Ikeda K, Friedman SL.: "Liver fibrosis and DDR2 signaling."Connective Tissue. 35. 165-168 (2003)

Ikeda K、Friedman SL.：“肝纤维化和 DDR2 信号传导。”结缔组织。

Inagaki Y, et al.: "Interferon alfa down-regulates collagen gene transcription and suppresses experimental hepatic fibrosis in mice."Hepatology.. 38. 890-899 (2003)

Inagaki Y 等人：“干扰素 α 下调胶原基因转录并抑制小鼠实验性肝纤维化。”Hepatology.. 38. 890-899 (2003)

Sato EF, Higashino M, Ikeda K, Wake R, Matsuo M, Utsumi K, Inoue M.: "Oxidative stress-induced cell death of human oral neutrophils"Am J Physiol Cell Physiol. 284(4). C1048-C1053 (2003)

Sato EF、Higashino M、Ikeda K、Wake R、Matsuo M、Utsumi K、Inoue M.：“氧化应激诱导的人口腔中性粒细胞死亡”Am J Physiol Cell Physiol。