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Raf-1 activates MAP kinase-kinase

Nature volume 358, pages 417–421 (1992)Cite this article

Abstract

THE normal cellular homologue of the acutely transforming oncogene v-ra/is c-raf-l, which encodes a serine/threonine protein kinase that is activated by many extracellular stimuli1. The physiological substrates of the protein c-Raf-1 are unknown. The mitogen-activated protein (MAP) kinases ErkI and 2 are also activated by mitogens through phosphorylation of Erk tyrosine and threonine residues catalysed by a protein kinase of relative molecular mass 50,000, MAP kinase-kinase (MAPK-K)2–7. Here we report that MAPK-K as well as Erkl and 2 are constitutively active in v-raf-transformed cells. MAPK-K partially purified from v-raf-transformed cells or from mitogen-treated cells3 can be deactivated by phosphatase 2A. c-Raf-1 purified after mitogen stimulation can reactivate the phosphatase 2A-inactivated MAPK-K over 30-fold in vitro. c-Raf-1 reactivation of MAPK-K coincides with the selective phosphorylation at serine/threonine residues of a polypeptide with Mr 50,000 which coelutes precisely on cation-exchange chromatography with the MAPK-K activatable by c-Raf-1. These results indicate that c-Raf-1 is an immediate upstream activator of MAPK-K in vivo. To our knowledge, MAPK-K is the first physiological substrate of the c-raf-l protooncogene product to be identified.

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Author notes

  1. Harald App and Ulf R. Rapp: Laboratory of Viral Carcinogenesis, National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, Maryland 21702, USA

  2. David L. Brautigan: Division of Biology and Medicine, Brown University, Providence, Rhode Island 02912, USA

Affiliations

  1. Diabetes Unit, Medical Services, Massachusetts General Hospital, 149 13th Street, Charlestown, Massachusetts, 02129

    John M. Kyriakis, Harald App, Xian-feng Zhang, Papia Banerjee, David L. Brautigan, Ulf R. Rapp & Joseph Avruch

  2. Department of Medicine, Harvard Medical School, Boston, Massachusetts, 02114, USA

    John M. Kyriakis, Harald App, Xian-feng Zhang, Papia Banerjee, David L. Brautigan, Ulf R. Rapp & Joseph Avruch

Authors
  1. John M. Kyriakis
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Kyriakis, J., App, H., Zhang, Xf. et al. Raf-1 activates MAP kinase-kinase. Nature 358, 417–421 (1992). https://doi.org/10.1038/358417a0

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