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Activation of the MAP kinase pathway by the protein kinase raf

L R Howe1, S J Leevers, N Gómez

  • 1Chester Beatty Laboratories, Institute of Cancer Research, London, England.

Cell
|October 16, 1992
PubMed

Insights

This study reveals that raf protein kinase acts upstream of MAP kinases. Raf is identified as a key component in the signaling pathway, potentially a MAP kinase kinase kinase or kinase kinase kinase.

Area of Science:

  • Cellular signaling pathways
  • Protein kinase interactions
  • Oncogene research

Background:

  • Mitogen-activated protein (MAP) kinases and p74raf-1 protein kinase are activated by growth factors and oncogenic p21ras.
  • The precise relationship between MAP kinases and raf signaling has not been fully elucidated.

Purpose of the Study:

  • To investigate the relationship between MAP kinases and raf protein kinase.
  • To determine the position of raf within the MAP kinase signaling cascade.

Main Methods:

  • Investigated MAP kinase ERK2 activation by oncogenically activated raf.
  • Examined the potentiation of ERK2 activation by overexpressed p74raf-1.
  • Assessed the reactivation of inactivated MAP kinase kinase by p74raf-1.

Main Results:

  • Oncogenic raf expression activates MAP kinase ERK2 independently of cellular ras.
  • Overexpressed p74raf-1 enhances ERK2 activation induced by EGF and TPA.
  • p74raf-1 immunoprecipitated from treated cells reactivates phosphatase-inactivated MAP kinase kinase.

Conclusions:

  • Raf protein kinase functions upstream of MAP kinases in cellular signaling.
  • Raf is proposed to be a MAP kinase kinase kinase or a MAP kinase kinase kinase kinase.

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