title: Plasma membrane nanoswitches generate high-fidelity Ras signal transduction.
abstract: Ras proteins occupy dynamic plasma membrane nanodomains called nanoclusters. The significance of this spatial organization is unknown. Here we show, using in silico and in vivo analyses of mitogen-activated protein (MAP) kinase signalling, that Ras nanoclusters operate as sensitive switches, converting graded ligand inputs into fixed outputs of activated extracellular signal-regulated kinase (ERK). By generating Ras nanoclusters in direct proportion to ligand input, cells build an analogue-digital-analogue circuit relay that transmits a signal across the plasma membrane with high fidelity. Signal transmission is completely dependent on Ras spatial organization and fails if nanoclustering is abrogated. A requirement for high-fidelity signalling may explain the non-random distribution of other plasma membrane signalling complexes.
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, Brisbane 4072, Australia.
authors.forename: Tianhai
authors.initials: T
authors.lastname: Tian
authors.forename: Angus
authors.initials: A
authors.lastname: Harding
authors.forename: Kerry
authors.initials: K
authors.lastname: Inder
authors.forename: Sarah
authors.initials: S
authors.lastname: Plowman
authors.forename: Robert G
authors.initials: RG
authors.lastname: Parton
authors.forename: John F
authors.initials: JF
authors.lastname: Hancock
mesh_terms: D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004789:Enzyme Activation; D020935:MAP Kinase Signaling System / Q000502:physiology*; D021962:Membrane Microdomains / Q000737:chemistry / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D008962:Models, Theoretical; D049329:Nanostructures; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D048490:raf Kinases / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D011993:Recombinant Fusion Proteins; D048490:raf Kinases; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins