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ARAF acts as a scaffold to stabilize BRAF:CRAF heterodimers

Oncogene volume 32, pages 3207–3212 (2013)Cite this article

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Abstract

The RAF proteins are cytosolic protein kinases that regulate cell responses to extracellular signals. There are three RAF proteins in cells, ARAF, BRAF and CRAF, and recent studies have shown that the formation of complexes by these different isoforms has an important role in their activation, particularly in response to RAF inhibitors. Here, we investigated the role of ARAF in cancer cell signaling and examined the role of ARAF in mediating paradoxical activation of the MAPK pathway in cells treated with RAF inhibitors. We show that two mutations that occur in ARAF in cancer inactivate the kinase. We also show that ARAF is not functionally redundant with CRAF and cannot substitute for CRAF downstream of RAS. We further show that ARAF binds to and is activated by BRAF and that ARAF also forms complexes with CRAF. Critically, ARAF seems to stabilize BRAF:CRAF complexes in cells treated with RAF inhibitors and thereby regulate cell signaling in a subtle manner to ensure signaling efficiency.

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Acknowledgements

This work was funded by Fundação para a Ciência e Tecnologia (SFRH/BD/15904/2005), the Institute of Cancer Research and Cancer Research UK (Ref: C107/A10433). We thank Professor Caroline Springer for providing sorafenib and PD184352.

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Author notes

  1. A P Rebocho

    Present address: 2Current address: Department of Biochemistry, Cambridge University, 80 Tennis Court Road, Cambridge CB2 1GA, UK.,

  2. R Marais

    Present address: 3Current address: Paterson Institute for Cancer Research, University of Manchester, Manchester, UK.,

Authors and Affiliations

  1. Division of Cancer Biology, Signal Transduction Team, The Institute of Cancer Research, London, UK

    A P Rebocho & R Marais

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  1. A P Rebocho
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  2. R Marais
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Correspondence to R Marais.

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Rebocho, A., Marais, R. ARAF acts as a scaffold to stabilize BRAF:CRAF heterodimers. Oncogene 32, 3207–3212 (2013). https://doi.org/10.1038/onc.2012.330

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