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

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 in duced in stellate cells activated by primary culture or in vivo during live r injury. The receptor becomes tyrosine phosphorylated in response to eithe r endogenous or exogenous type I collagen, whereas its expression is downre gulated during cellular quiescence induced by growth on Matrigel. We develo ped stellate cell lines stably overexpressing either wild-type DDR2, a cons titutively active chimeric DDR2 receptor (Fc-DDR2), a truncated receptor ex pressing the extracellular domain, or a kinase-dead DDR2 Cells overexpressi ng DDR2 showed enhanced proliferation and invasion through Matrigel, activi ties that were directly related to increased expression of active matrix me talloproteinase 2 (MMP-2). These data show that DDR2 is induced during stel late cell activation and implicate the phosphorylated receptor as a mediato r of MMP-2 release and growth stimulation in response to type I collagen. M oreover, type I collagen-dependent upregulation of DDR2 expression establis hes a positive feedback loop in activated stellate cells, leading to furthe r proliferation and enhanced invasive activity.