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Mechanistic principles of RAF kinase signaling

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Abstract

The RAF family of kinases are key components acting downstream of receptor tyrosine kinases and cells employ several distinct mechanisms to strictly control their activity. RAF transitions from an inactive state, where the N-terminal regulatory region binds intramolecularly to the C-terminal kinase domain, to an open state capable of executing the phosphoryl transfer reaction. This transition involves changes both within and between the protein domains in RAF. Many different proteins regulate the transition between inactive and active states of RAF, including RAS and KSR, which are arguably the two most prominent regulators of RAF function. Recent developments have added several new twists to our understanding of RAF regulation. Among others, dimerization of the RAF kinase domain is emerging as a crucial step in the RAF activation process. The multitude of regulatory protein–protein interactions involving RAF remains a largely untapped area for therapeutic applications.

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Acknowledgments

This work was supported by funding from the Canadian Institutes for Health Research and from the Canadian Cancer Society to M.T. and F.S. T.R. is a Research Fellow of The Terry Fox Foundation. F.S. holds a Canada Research Chair in Structural Biology of Signal Transduction, and M.T. is a Canada Research Chair (Tier II) in Intracellular Signaling.

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  1. Laboratory of Intracellular Signaling, Département de pathologie et de biologie cellulaire, Institute for Research in Immunology and Cancer, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montreal, QC, H3C 3J7, Canada

    Christian M. Udell & Marc Therrien

  2. Centre for Systems Biology, Samuel Lunenfeld Research Institute, Toronto, ON, M5G 1X5, Canada

    Thanashan Rajakulendran & Frank Sicheri

  3. Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada

    Thanashan Rajakulendran & Frank Sicheri

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  1. Christian M. Udell
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  4. Marc Therrien
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Correspondence to Marc Therrien.

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Udell, C.M., Rajakulendran, T., Sicheri, F. et al. Mechanistic principles of RAF kinase signaling. Cell. Mol. Life Sci. 68, 553–565 (2011). https://doi.org/10.1007/s00018-010-0520-6

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  • DOI: https://doi.org/10.1007/s00018-010-0520-6

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