The hepatocyte growth factor receptor kinase-mediated phosphorylation of lipocortin-1 transduces the proliferating signal of the hepatocyte growth factor.

Hepatocyte growth factor (HGF), which is identical to scatter factor (SF) through coupling to its receptor the product of c-met oncogene, was found to induce proliferation of A549 lung carcinoma cell line, accompanied by release of prostaglandin E2 (PGE2). This activity was sensitive to 0.1-100 microM indomethacin and to 5-50 nM of verapamil. Lipocortin-1, a dexamethasone-inducible inhibitor of phospholipase A2, was shown to be phosphorylated on tyrosine 10 min upon addition of HGF and to translocate to the membrane fraction for up to 6 h upon ligand stimulation. Lipocortin-1 was found to associate in vivo with the HGF receptor species, and this association was independent of the phosphorylation state of the beta-subunit of the HGF receptor (p145betaMET. Immobilized HGF receptor kinase species associated and phosphorylated in vitro lipocortin-1, thus providing evidence that lipocortin-1 is directly phosphorylated by the p145betaMET. Incubation of A549 cells with antisense 21-mer lipocortin-1 oligonucleotides reduced the synthesis and the HGF-stimulated phosphorylation of lipocortin-1 as well as the HGF-stimulated cell proliferation. In processes where the HGF receptor tyrosine kinase is activated, phosphorylation of lipocortin-1 may function as a "signal amplifier" promoting the release of intercellular messengers (PGE2) with pluripotent roles in cell proliferation, chemotaxis, and vascular remodeling.