DDR2 receptor promotes AMP-2-mediated proliferation and invasion by hepatic stellate cells
DDR2 receptor promotes AMP-2-mediated proliferation and invasion by hepatic stellate cells
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DOI：
10.1172/jci12373
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发表时间：
2001-11-01
影响因子：
15.9
通讯作者：
Friedman, SL
中科院分区：
文献类型：
--
作者：
Olaso, E;Ikeda, K;Friedman, SL
I型胶原通过尚不清楚的机制在肝损伤期间引起肝星状细胞的活化。在这里，我们测试了盘状结构域酪氨酸激酶受体2（DDR2）的作用，它的信号响应于I型胶原蛋白，在这一途径中。DDR2 mRNA和蛋白在通过原代培养或在肝损伤期间在体内活化的星状细胞中被诱导。受体成为酪氨酸磷酸化的内源性或外源性I型胶原蛋白的反应，而其表达在细胞静止诱导生长基质胶。我们开发了稳定过表达野生型DDR2、组成型活性嵌合DDR2受体（Fc-DDR2）、表达细胞外结构域的截短受体或激酶死亡DDR2的星状细胞系。过表达DDR2的细胞通过基质胶表现出增强的增殖和侵袭，活性与活性基质金属蛋白酶2（MMP-2）的表达增加直接相关。这些数据表明，DDR2在星状细胞活化过程中被诱导，并暗示磷酸化受体作为MMP-2释放和生长刺激的介体响应于I型胶原。此外，DDR2表达的I型胶原依赖性上调在活化的星状细胞中建立了正反馈回路，导致进一步增殖和增强的侵袭活性。
Type I collagen provokes activation of hepatic stellate cells during liver injury through mechanisms that have been unclear. Here, we tested the role of the discoidin domain tyrosine kinase receptor 2 (DDR2), which signals in response to type I collagen, in this pathway. DDR2 mRNA and protein are induced in stellate cells activated by primary culture or in vivo during liver injury. The receptor becomes tyrosine phosphorylated in response to either endogenous or exogenous type I collagen, whereas its expression is downregulated during cellular quiescence induced by growth on Matrigel. We developed stellate cell lines stably overexpressing either wild-type DDR2, a constitutively active chimeric DDR2 receptor (Fc-DDR2), a truncated receptor expressing the extracellular domain, or a kinase-dead DDR2 Cells overexpressing DDR2 showed enhanced proliferation and invasion through Matrigel, activities that were directly related to increased expression of active matrix metalloproteinase 2 (MMP-2). These data show that DDR2 is induced during stellate cell activation and implicate the phosphorylated receptor as a mediator of MMP-2 release and growth stimulation in response to type I collagen. Moreover, type I collagen-dependent upregulation of DDR2 expression establishes a positive feedback loop in activated stellate cells, leading to further proliferation and enhanced invasive activity.