Plasmin decreases the BH3-only protein BimEL via the ERK1/2 signaling pathway in hepatocytes

Since the signal transduction mechanisms responsible for liver regeneration mediated by the plasminogen/plasmin system remain largely undetermined, we have investigated whether plasmin regulates the pro-apoptotic protein BimEL in primary hepatocytes. Plasmin bound to hepatocytes in part via its lysine binding sites (LBS). Plasmin also triggered phosphorylation of ERK1/2 without cell detachment. The plasmin-induced phosphorylation of ERK1/2 was inhibited by the LBS inhibitor epsilon-aminocaproic acid (EACA), the serine protease inhibitor aprotinin, and the MEK inhibitor PD98059. DFP-inactivated plasmin failed to phosphorylate ERK1/2. Plasmin temporally decreased the starvation-induced expression of BimEL and activation of caspase-3 via the ERK1/2 signaling pathway, resulting in an enhancement of cell survival. The amount of mRNA for Bim increased 1 day after the injection of CCl4 in livers of plasminogen knockout (Plg-KO) and the wild-type (WT) mice. The increase in BimEL protein persisted for at least 7 days post-injection in livers of Plg-KO mice, whereas WT mice showed an increase in BimEL protein 1 day after the injection. Plg-KO and WT mice showed notable phosphorylation of ERK1/2 7 and 3 days after the injection of CCl4, respectively. Our data suggest that the plasminogen/plasmin system could decrease BimEL expression via the ERK1/2 signaling pathway during liver regeneration.