Inhibitory actions of cyclic adenosine monophosphate and pertussis toxin define two distinct epidermal growth factor–regulated pathways leading to activation of mitogen-activated protein kinase in rat hepatocytes
✍ Scribed by P Gines; X Li; S E Brown; T Nakamura; P S Guzelian; L E Heasley; R W Schrier; R A Nemenoff
- Publisher
- John Wiley and Sons
- Year
- 1996
- Tongue
- English
- Weight
- 589 KB
- Volume
- 23
- Category
- Article
- ISSN
- 0270-9139
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✦ Synopsis
ter pathway probably involves a pertussis toxin-sensi-Increased intracellular cyclic adenosine monophostive G protein. (HEPATOLOGY 1996;23:1167-1173.) phate (cAMP) levels have been shown in some reports to inhibit and in other studies to stimulate growth factormediated activation of the mitogen-activated protein kinase (MAP kinase) pathway, depending on the cell type Epidermal growth factor (EGF) 1 and hepatocyte examined. The relationship between cAMP and MAP kigrowth factor (HGF) are among the most potent mitonase in hepatocytes has not been examined. In the curgens for hepatocytes in culture and are likely to play rent study, stimulation of primary cultures of rat hepatoan important role in normal liver growth and liver recytes with hepatocyte growth factor (HGF) or epidermal generation. 2-6 However, the postreceptor signaling growth factor (EGF) increased Ras, Raf, and MAP kinase pathways mediating the effects of these agents are not activity. Incubation of hepatocytes with cAMP-increaswell understood. It has been shown that both EGF and ing agents blocked activation of Raf by both HGF and EGF, whereas activation of Ras was unaffected. MAP HGF activate phospholipase Cg in hepatocytes, rekinase activation by HGF was completely inhibited, sulting in increased production of inositol phosphates whereas EGF-stimulated MAP kinase activity was only and mobilization of intracellular Ca 2/ . [7][8][9][10][11][12] In addition, slightly reduced. Incubation of hepatocytes with pertuswe have recently shown that both EGF and HGF stimusis toxin slightly blunted MAP kinase activation by EGF late Raf and mitogen-activated protein kinase (MAP but not HGF. Increasing cAMP in hepatocytes preincukinase) activity in rat hepatocytes. 13 The precise physibated with pertussis toxin completely inhibited the actiological role of the activation of the MAP kinase pathvation of MAP kinase by EGF. In conclusion, HGF actiway in hepatocytes is not known, but given the imporvates MAP kinase in hepatocytes exclusively through tance of this pathway in the control of cell proliferation an Raf-dependent pathway and this activation may be and differentiation in many other cell types, [14][15][16] it probcompletely blocked by increasing cAMP. In contrast, EGF activates MAP kinase in hepatocytes through both ably plays an important role in the regulation of hepa-Raf-dependent and Raf-independent pathways: the lattocyte growth.
Several recent studies have shown that cyclic adenosine monophosphate (cAMP) inhibits growth factor-Abbreviations: EGF, epidermal growth factor; HGF, hepatocyte growth facmediated activation of the MAP kinase pathway. Intor; MAP, mitogen-activated protein; cAMP, cyclic adenosine monophosphate; creased concentrations of cAMP block the activation of SDS, sodium dodecyl sulfate; GTP, guanosine triphosphate. several kinases of the MAP kinase pathway, including