title: Subcellular localization determines MAP kinase signal output.
abstract: The Raf-MEK-ERK MAP kinase cascade transmits signals from activated receptors into the cell to regulate proliferation and differentiation. The cascade is controlled by the Ras GTPase, which recruits Raf from the cytosol to the plasma membrane for activation. In turn, MEK, ERK, and scaffold proteins translocate to the plasma membrane for activation. Here, we examine the input-output properties of the Raf-MEK-ERK MAP kinase module in mammalian cells activated in different cellular contexts. We show that the MAP kinase module operates as a molecular switch in vivo but that the input sensitivity of the module is determined by subcellular location. Signal output from the module is sensitive to low-level input only when it is activated at the plasma membrane. This is because the threshold for activation is low at the plasma membrane, whereas the threshold for activation is high in the cytosol. Thus, the circuit configuration of the module at the plasma membrane generates maximal outputs from low-level analog inputs, allowing cells to process and respond appropriately to physiological stimuli. These results reveal the engineering logic behind the recruitment of elements of the module from the cytosol to the membrane for activation.
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, Brisbane 4072, Australia.
authors.forename: Angus
authors.initials: A
authors.lastname: Harding
authors.forename: Tianhai
authors.initials: T
authors.lastname: Tian
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Westbury
authors.forename: Ester
authors.initials: E
authors.lastname: Frische
authors.forename: John F
authors.initials: JF
authors.lastname: Hancock
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D006224:Cricetinae; D003600:Cytosol / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology*; D005812:Genes, Switch / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008856:Microscopy, Fluorescence; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D014162:Transfection; D048490:raf Kinases / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
chemical_list: D048490:raf Kinases; D020928:Mitogen-Activated Protein Kinases; D010744:Phosphoric Monoester Hydrolases; D018631:ras Proteins