Structural keys unlock RAS–MAPK cellular signalling pathway

Lavoie, Hugo; Therrien, Marc

doi:10.1038/d41586-022-02189-7

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15 August 2022

Structural keys unlock RAS–MAPK cellular signalling pathway

Activation of the RAF protein is key to the RAS–MAPK signalling pathway, and involves the SMP protein complex. Structures for SMP shed light on the process, and suggest fresh targets for anticancer drug discovery.

Hugo Lavoie⁰ &
Marc Therrien¹

Hugo Lavoie
1. Hugo Lavoie is at the Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec H3C 3J7, Canada.
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Marc Therrien
1. Marc Therrien is at the Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec H3C 3J7, Canada.
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Unbridled activation of an intracellular signalling network called the RAS–MAPK pathway is the cause of several cancers and of developmental syndromes known as RASopathies¹. This well-studied pathway (reviewed in ref. 2) starts with a membrane-bound RAS GTPase enzyme — HRAS, KRAS or NRAS — that, when activated by extracellular growth-factor proteins, binds to the nucleotide molecule GTP. RAS–GTP contacts physically and activates a kinase enzyme called RAF, triggering a signalling cascade that leads to activation of another kinase, MAPK. This enzyme, in turn, modulates the activity of proteins involved in many cellular processes. How RAS activates RAF has been the focus of much research. Writing in Nature, Liau et al.³, Kwon et al.⁴ and Hauseman et al.⁵ shed light on this crucial step by independently reporting the structure of a protein complex involved in RAF activation.

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Nature 609, 248-249 (2022)

doi: https://doi.org/10.1038/d41586-022-02189-7

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