Plasma membrane nanoswitches generate high-fidelity Ras signal transduction.
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.
Tian
Tianhai
T
Institute for Molecular Bioscience, University of Queensland, Brisbane 4072, Australia.
Harding
Angus
A
Inder
Kerry
K
Plowman
Sarah
S
Parton
Robert G
RG
Hancock
John F
JF
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*
D011993:Recombinant Fusion Proteins; D048490:raf Kinases; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins