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Related Experiment Videos

Raf-1 activates MAP kinase-kinase.

J M Kyriakis1, H App, X F Zhang

  • 1Diabetes Unit, Medical Services, Massachusetts General Hospital, Charlestown 02129.

Nature
|July 30, 1992
PubMed
Summary
This summary is machine-generated.

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The c-raf-1 protooncogene product, a serine/threonine protein kinase, directly activates MAP kinase-kinase (MAPK-K). This finding identifies MAPK-K as the first physiological substrate of c-Raf-1, clarifying a key step in cellular signaling pathways.

Area of Science:

  • Cellular Biology
  • Molecular Oncology
  • Signal Transduction

Background:

  • The c-raf-1 protooncogene encodes a serine/threonine protein kinase activated by extracellular stimuli.
  • The physiological substrates of c-Raf-1, a key signaling molecule, remain largely unknown.
  • Mitogen-activated protein (MAP) kinases Erk1 and Erk2 are activated via phosphorylation by MAP kinase-kinase (MAPK-K).

Purpose of the Study:

  • To identify the physiological substrates of the c-Raf-1 protein kinase.
  • To investigate the role of c-Raf-1 in the activation of MAPK-K and Erk1/2.
  • To elucidate the upstream activators of MAPK-K in cellular signaling.

Main Methods:

  • Analysis of constitutively active MAPK-K and Erk1/2 in v-raf-transformed cells.
  • Enzymatic assays using partially purified MAPK-K and phosphatase 2A.

Related Experiment Videos

  • In vitro kinase assays with purified c-Raf-1 to assess MAPK-K reactivation.
  • Cation-exchange chromatography to characterize MAPK-K and its interaction with c-Raf-1.

    • Main Results:

    • MAPK-K and Erk1/2 were found to be constitutively active in v-raf-transformed cells.
    • Phosphatase 2A deactivated MAPK-K, but purified c-Raf-1 could reactivate it in vitro.
    • c-Raf-1 mediated the selective phosphorylation of a 50,000 M(r) polypeptide co-eluting with MAPK-K.
    • These findings demonstrate c-Raf-1 as an immediate upstream activator of MAPK-K.

    Conclusions:

    • c-Raf-1 is identified as the direct upstream activator of MAPK-K.
    • MAPK-K is the first identified physiological substrate of the c-raf-1 protooncogene product.
    • This study clarifies a critical step in the MAP kinase signaling cascade regulated by c-Raf-1.