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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Article

DDR2 receptor promotes MMP-2–mediated proliferation and invasion by hepatic stellate cells

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 1

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DDR2 is induced during stellate cell activation in vitro. Stellate cells...
DDR2 is induced during stellate cell activation in vitro. Stellate cells isolated from normal rat livers were maintained in monolayer culture for up to 8 days, and DDR2 mRNA and protein were analyzed. (a) Northern blot analysis performed with 10 μg mRNA from primary cultures of stellate cells hybridized to DDR2 and GAPDH cDNAs. (b) Summary histogram showing the induction of DDR2 during stellate cell activation by in vitro culture based on data from a. Results are expressed as a ratio of DDR2 mRNA versus GAPDH mRNA. (c) Stellate cells were cultured for 0, 2, and 8 days, lysed in RIPA buffer, immunoprecipitated, immunoblotted, and probed with the polyclonal anti-DDR2 Ab R2-JM. COS-1 cells were transfected with full-length DDR2 (+) or empty vector (–). (d) Lysates were also analyzed by Western blot for tubulin as a control for protein loading.