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

Abstract

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 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 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␤

Hepatocyte Growth Factor/Scatter Factor-induces phosphorylation of cortactin in A431 cells in a Src kinase-independent manner

“…Src kinases are actively involved in mediating the HGF/SF motility signal and a double mutant of c-Src signi®cantly a ected the HGF/SF-induced motility of SP1 intraductal cells over-expressing HGF/SF and MET (Rahimi et al, 1998). Moreover, the Met receptor is reported to phosphorylate downstream targets not possessing SH2 domains and without the mediation of Src or other intracellular kinases (Cbl, lipocortin) Skouteris and SchroÈ der, 1996). In addition to that, Gab1 binds the bidentate docking site of MET via its proline-rich domain (Met-binding domain, MBD) located within amino acid residues 450 ± 532 (Weidner et al, 1996).…”

Annexin-1 Regulates Growth Arrest Induced by High Levels of Estrogen in MCF-7 Breast Cancer Cells

“…4; for a review, see ref. 6) through the modulation of mitogen-activated protein kinase signaling, calcium ion mobilization, apoptosis (5), cell proliferation (8,9), and inhibition of cell growth (10,11).…”

Specific association of annexin 1 with plasma membrane‐resident and internalized EGF receptors mediated through the protein core domain

“…The N-terminal domain of annexin 1 contains phosphorylation sites for protein kinase C and several tyrosine kinases including the epidermal growth factor (EGF) receptor tyrosine kinase, which phosphorylates tyrosine 21 [7][8][9][10]. Phosphorylation of the protein, which is induced by growth factors and cytokines, including EGF, insulin, HGF, growth hormone, and angiotensin II [2,[11][12][13][14], is reported to participate in mediating or regulating the mitogenic response [15,16]. Annexin 1 is highly expressed and phosphorylated during hepatocarcinoma development and has been implicated in liver regeneration and tumorigenesis, probably by modulating EGF receptor (EGFR) activity [17].…”