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SIGNAL TRANSDUCTION

Building insights into KRAS signaling complexes

Nature Structural & Molecular Biology volume 28, pages 773–774 (2021)Cite this article

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The critical event in KRAS signaling and oncogenic transformation is activation of the RAF–MEK–MAPK cascade. This requires assembly of a multiprotein–lipid complex on the plasma membrane. In a tour de force of modeling, Mysore et al. now provide the first glimpse of what this structure may actually look like.

KRAS is a membrane-localized GTPase that oscillates between active GTP-bound and inactive GDP-bound states and functions as a critical node in growth factor receptor signaling pathways. To generate an output signal, KRAS must recruit effector proteins from the cytosol for activation. One example is the MAPK cascade, whereby KRAS recruits RAF to the plasma membrane for activation, in turn triggering the activation of MEK and ERK. In this issue of Nature Structural & Molecular Biology, Mysore et al.1 use molecular dynamics (MD) simulations to devise a fascinating model of this activation complex, which they term a signalosome, that accommodates the membrane; KRAS; the core kinases CRAF, MEK and ERK; and the ancillary regulatory components GAL3 and 14-3-3.

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Authors and Affiliations

  1. Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA

    John F. Hancock & Alemayehu A. Gorfe

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  1. John F. Hancock
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  2. Alemayehu A. Gorfe
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Correspondence to John F. Hancock or Alemayehu A. Gorfe.

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Hancock, J.F., Gorfe, A.A. Building insights into KRAS signaling complexes. Nat Struct Mol Biol 28, 773–774 (2021). https://doi.org/10.1038/s41594-021-00631-4

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