Uncoupling of Hepatic, Epidermal Growth Factor-mediated Mitogen-activated Protein Kinase Activation in the Fetal Rat

These findings indicate that a novel negative feedback mechanism for mitogenactivated protein kinase regulation may be active in developing rat hepatocytes

Joan M. Boylan; Philip A. Gruppuso

2002

Scholarcy highlights

  • A major signaling pathway through which virtually all known mitogens exert intracellular responses is the mitogenactivated protein1 kinase cascade
  • In our initial studies, we demonstrated that intraperitoneal injection of epidermal growth factor2 into E19 fetuses or adult rats resulted in the activation of the proximal portion of the EGF signaling pathway in the liver
  • Our prior observation that intraperitoneal injection of late gestation fetal rats in situ with EGF showed only minimal activation of hepatic MAP kinases was initially interpreted as indicating a probable block at the level of Ras activation. This was based on observations from several laboratories indicating that growth factor activation of the MAP kinase pathway can lead to phosphorylation of the Ras guanyl nucleotide exchange protein SOS, thereby down-regulating the MAP kinase pathway
  • Such a mechanism might pertain to negative feedback inhibition of hepatic MAP kinase activation in the growth factor-rich fetal environment
  • The ability of EGF to activate hepatic MAP kinases in vivo was recovered during the early phase of postnatal development, a period when hepatocyte proliferation is slowing and fetal hepatocytes are making the transformation to an adult hepatocyte phenotype
  • The observation that Raf and MEK activation were intact in the absence of MAP kinase activation indicated an alternative regulatory mechanism
  • These findings do not rule out a fetal hepatic mitogenactivated protein kinase phosphatase as the factor required for uncoupling of MAP kinase activation from MEK activation, they do not support this hypothesis

Need more features? Save interactive summary cards to your Scholarcy Library.