ERK1/2 and JNK signaling synergistically modulate mitogenic effect of fibroblast growth factor 2 on liver cell

Proliferation of the adult hepatocyte population represents a central feature of tissue regeneration after liver injury and resection. This process could be driven by a diverse range of mitogens, such as hepatocyte growth factor (HGF) and fibroblast growth factor (FGF). Among FGF family, FGF2 is closely related to wound repair and cell proliferation. FGF2 does function in the process of angiogenesis in regenerating liver, while fewer reports are concerned with the impact and underlying mechanism of FGF2 on liver cell proliferation. To this end, an immortalized human normal hepatocyte L02 and mouse primary hepatocytes were exposed to FGF2 in this study. We demonstrate that FGF2 significantly enhances liver cell proliferation. Treatment with FGF2 obviously increases the phosphorylation level of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and c-Jun N-terminal kinase (JNK). Activity inhibition or expression down-regulation prove that both ERK1/2 and JNK signaling are required for FGF2-mediated effect on liver cell proliferation. Interestingly, interfering of ERK1/2 signaling results in marked decrease of JNK activation under FGF2 treatment, and JNK signaling is also involved in regulation of FGF2-induced ERK1/2 activation, suggesting that cross-talk between ERK1/2 and JNK signaling is important for FGF2 mitogenic activity. Both ERK1/2 and JNK signal via CREB to function in proliferation impact of FGF2 on liver cells. Taken together, this study reveals that ERK and JNK pathways synergistically regulate FGF2-induced liver cell proliferation via phosphorylating CREB, which will contribute to the understanding of FGF2 impact on liver cell proliferation and liver regeneration.