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DDR2 receptor promotes MMP-2–mediated proliferation and invasion by hepatic stellate cells
Elvira Olaso, … , Hsin Chieh Lin, Scott L. Friedman
Elvira Olaso, … , Hsin Chieh Lin, Scott L. Friedman
Published November 1, 2001
Citation Information: J Clin Invest. 2001;108(9):1369-1378. https://doi.org/10.1172/JCI12373.
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DDR2 receptor promotes MMP-2–mediated proliferation and invasion by hepatic stellate cells

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Abstract

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.

Authors

Elvira Olaso, Kazuo Ikeda, Francis J. Eng, Lieming Xu, Li-Hsien Wang, Hsin Chieh Lin, Scott L. Friedman

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Figure 2

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DDR2 is induced in stellate cells during liver injury. (a) Northern blot...
DDR2 is induced in stellate cells during liver injury. (a) Northern blot analysis of DDR2 mRNA expression in rat stellate cells isolated after administration of a single dose of CCl4 or after bile duct ligation. (b) Summary histogram demonstrating the induction of DDR2 during liver injury. Results are expressed in the histograms as the ratio of DDR2 mRNA versus GAPDH mRNA. (c) Total liver extracts from rats treated 4 weeks with CCl4 or corn oil vehicle alone were lysed in RIPA buffer. DDR2 was immunoprecipitated with the R2-JM Ab, followed by Western blot analysis with an anti-phosphotyrosine Ab (4G10) or the anti-DDR2 Ab R2-JM.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 33 patents
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