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Volume 271, Number 44, Issue of November 1, 1996 pp. 27266-27273
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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The Hepatocyte Growth Factor Receptor Kinase-mediated Phosphorylation of Lipocortin-1 Transduces the Proliferating Signal of the Hepatocyte Growth Factor

(Received for publication, May 7, 1996, and in revised form, August 9, 1996)

From the Division of Virus-Host Interactions, Research Program of Applied Tumor Virology, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 242, D-69120 Heidelberg, Germany

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 µM 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 -subunit of the HGF receptor (p145^MET. Immobilized HGF receptor kinase species associated and phosphorylated in vitro lipocortin-1, thus providing evidence that lipocortin-1 is directly phosphorylated by the p145^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 (PGE₂) with pluripotent roles in cell proliferation, chemotaxis, and vascular remodeling.

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