A comparative study of the hepatic mitogen-activated protein kinase and Jun-NH2-terminal kinase pathways in the late-gestation fetal rat.

Mitogen-activated protein kinases (MAPKs) and Jun-NH2-terminal kinases (JNKs) are considered members of parallel but separate signal transduction cascades. We have compared the regulation and, indirectly, the role of these two pathways in hepatic development during late gestation in the rat. Our initial experiments showed that the two pathways crossed over to a significant degree. Both could be activated in primary cultures of fetal rat hepatocytes by exposure to transforming growth factor alpha (TGF-alpha), a potent MAPK activator, or tumor necrosis factor alpha (TNF-alpha), a potent JNK activator. Fractionation of fetal hepatocyte lysates showed that the same MAPKs were stimulated by TGF-alpha as by TNF-alpha. In contrast, TGF-alpha activated only one JNK, whereas TNF-alpha stimulated multiple kinases with activity toward Jun. JNKs were found to be active under normal conditions in 19-day fetal liver compared with adult liver, whereas MAPK was not. Moreover, although JNKs could be activated further by intraperitoneal injection of TNF-alpha to the intact 19-day fetus, MAPKs could not be activated in vivo by i.p. injection of epidermal growth factor (EGF), which, like TGF-alpha, acts via the EGF receptor. EGF could not activate fetal hepatic MAPKs even though signal initiation was intact, as indicated by tyrosine phosphorylation of the adaptor protein Shc and Shc/Grb2 complex formation. These results indicate that the JNK-signaling pathway may support fetal hepatocyte proliferation in vivo. In contrast, MAPK signaling is uncoupled, possibly indicating that it is not involved in maintaining hepatocyte proliferation in the late-gestation rat.