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）是一种不寻常的酪氨酸激酶受体，因为它的配体是纤维胶原蛋白而不是生长因子样肽。我们测试了信号通路和DDR2的作用。在肝损伤过程中，DDR2 mRNA和蛋白在原代培养和活体激活的肝星状细胞中被诱导表达。受体对I型胶原蛋白产生酪氨酸磷酸化反应。DDR2的信号传导增加了活性基质金属蛋白酶2的表达。我们还发现DDR2的不同寻常之处在于它需要Src活性才能最大限度地酪氨酸磷酸化，并且Src活性还促进DDR2与接头蛋白Shc的关联。与Shc的相互作用涉及先前未与受体酪氨酸激酶相互作用的Shc的一部分。这些结果表明Src激酶和接头蛋白Shc是DDR2信号转导的关键信号中间体。为了进一步研究Src激酶与纤维化肝DDR2的关系，我们将受胶原1A2启动子调控的Src显性阴性表达腺载体注射到经硫代乙酰胺处理的大鼠体内。显性阴性Src过表达抑制DDR2磷酸化，减少组织学纤维化改变。这些数据支持Src和DDR2受体以一种受调控的方式合作来指导受体及其靶标的磷酸化的模型。

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)。

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)

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。

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。