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Rheb is in a high activation state and inhibits B-Raf kinase in mammalian cells

Oncogene volume 21, pages 6356–6365 (2002)Cite this article

Abstract

Rheb (Ras homolog enriched in brain) is a member of the Ras family of proteins, and is in the immediate Ras/Rap/Ral subfamily. We found in three different mammalian cell lines that Rheb was highly activated, to levels much higher than for Ras or Rap 1, and that Rheb's activation state was unaffected by changes in growth conditions. Rheb's high activation was not secondary to unique glycine to arginine, or glycine to serine substitutions at positions 14 and 15, corresponding to Ras residues 12 and 13, since Rheb R14G and R14G, S15G mutants had similarly high activation levels as wild type Rheb. These data are consistent with earlier work which showed that purified Rheb has similar GTPase activity as Ras, and suggest a relative intracellular deficiency of Rheb GTPase activating proteins (GAPs) compared to Rheb activators. Further evidence for relatively low intracellular GAP activity was that increased Rheb expression led to a marked increase in Rheb activation. Rheb, like Ras and Rap1, bound B-Raf kinase, but in contrast to Ras and Rap 1, Rheb inhibited B-Raf kinase activity and prevented B-Raf-dependent activation of the transcription factor Elk-1. Thus, Rheb appears to be a unique member of the Ras/Rap/Ral subfamily, and in mammalian systems may serve to regulate B-Raf kinase activity.

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Acknowledgements

This work was supported in part by USPHS Grants GM55586 (to RB Pilz), CA76968 and CA81115 (to GR Boss) and MH53608 (to PF Worley); E Im was supported by a UCSD Institute for Research on Aging Scholarship. We thank G Johnson, M Karin, L Quilliam, P Stork and M Wigler for generously providing the indicated plasmids.

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  1. Edward Im and Friederike C von Lintig: These two authors contributed equally to the work

Authors and Affiliations

  1. Department of Medicine and Cancer Center, University of California, San Diego, La Jolla, 92093-0652, California, CA, USA

    Edward Im, Friederike C von Lintig, Jeffrey Chen, Shunhui Zhuang, Wansong Qui, Gerry R Boss & Renate B Pilz

  2. Department of Neuroscience, Johns Hopkins University, Baltimore, 21205, Maryland, MD, USA

    Shoaib Chowdhury & Paul F Worley

  3. Department of Neurology, Johns Hopkins University, Baltimore, 21205, Maryland, MD, USA

    Shoaib Chowdhury & Paul F Worley

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  1. Edward Im
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  2. Friederike C von Lintig
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Correspondence to Renate B Pilz.

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Im, E., von Lintig, F., Chen, J. et al. Rheb is in a high activation state and inhibits B-Raf kinase in mammalian cells. Oncogene 21, 6356–6365 (2002). https://doi.org/10.1038/sj.onc.1205792

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