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 E(2) (PGE(2)), This activity was sensitive to 0.1-100 mu m indomethacin and to 5-50 nM of verapamil. Lipocortin-1, a dexamethasone-inducible inhibitor of phospholipase A(2), was shown to be phosphorylated on tyrosine 10 min upon addition of HGF and to translocate 60 the membrane fraction for up to 6 h upon ligand stimulation, Lipocortin-l was found to associate in vivo with the HGP receptor species, and this association was independent of the phosphorylation state of the beta-subunit of the HGF receptor (p145 beta(MET). ImmobiLized HGF receptor kinase species associated and phosphorylated in vitro lipocortin-1, thus providing evidence that lipocortin-l is directly phosphorylated by the p145 beta(MET). 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 (PGE(2)) with pluripotent roles in cell proliferation, chemotaxis, and vascular remodeling.