Scheving Lawrence A, Stevenson Mary C, Taylormoore Jonathan M, Traxler Peter, Russell William E
Department of Pediatrics, Medical Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Biochem Biophys Res Commun. 2002 Jan 11;290(1):197-203. doi: 10.1006/bbrc.2001.6157.
Hepatocyte growth factor (HGF), insulin, and TGF-alpha stimulate DNA synthesis in cultured hepatocytes. Each ligand activates a distinct tyrosine kinase receptor, although receptor cross-talk modulates signaling. In rat hepatocytes, HGF can stimulate TGF-alpha production while TGF-alpha antibodies or antisense oligonucleotides suppress HGF-stimulated DNA synthesis. We report that the epidermal growth factor receptor (EGFR) kinase inhibitor PKI166 blocked both basal and ligand-induced tyrosine phosphorylation of the EGFR (IC(50) = 60 nM), but not of the insulin receptor or c-met. Pharmacologic inhibition of the EGFR kinase abolished the proliferative actions of HGF and EGF, but not insulin, whereas PI-3 kinase inhibition blocked both EGF and insulin actions. We conclude that in cultured hepatocytes (i) PI-3 kinase is required for EGF- and insulin-induced proliferation and (ii) EGFR mediates both the basal rate of DNA synthesis and that induced by EGF and HGF, but not insulin. The mitogenic effect of HGF may be secondary to increased synthesis or processing of EGFR ligands such as TGF-alpha.
肝细胞生长因子（HGF）、胰岛素和转化生长因子α（TGF-α）可刺激培养的肝细胞中的DNA合成。尽管受体间相互作用会调节信号传导，但每种配体都会激活一种独特的酪氨酸激酶受体。在大鼠肝细胞中，HGF可刺激TGF-α的产生，而TGF-α抗体或反义寡核苷酸可抑制HGF刺激的DNA合成。我们报告，表皮生长因子受体（EGFR）激酶抑制剂PKI166可阻断EGFR的基础酪氨酸磷酸化和配体诱导的酪氨酸磷酸化（IC50 = 60 nM），但不影响胰岛素受体或c-met的酪氨酸磷酸化。对EGFR激酶的药理抑制作用消除了HGF和表皮生长因子（EGF）的增殖作用，但不影响胰岛素的增殖作用，而磷脂酰肌醇-3激酶（PI-3激酶）抑制作用则阻断了EGF和胰岛素的作用。我们得出结论，在培养的肝细胞中：（i）PI-3激酶是EGF和胰岛素诱导的增殖所必需的；（ii）EGFR介导DNA合成的基础速率以及由EGF和HGF诱导的DNA合成速率，但不介导胰岛素诱导的DNA合成速率。HGF的促有丝分裂作用可能继发于EGFR配体（如TGF-α）合成或加工的增加。
