title: Scaffold proteins may biphasically affect the levels of mitogen-activated protein kinase signaling and reduce its threshold properties.
abstract: In addition to preventing crosstalk among related signaling pathways, scaffold proteins might facilitate signal transduction by preforming multimolecular complexes that can be rapidly activated by incoming signal. In many cases, such as mitogen-activated protein kinase (MAPK) cascades, scaffold proteins are necessary for full activation of a signaling pathway. To date, however, no detailed biochemical model of scaffold action has been suggested. Here we describe a quantitative computer model of MAPK cascade with a generic scaffold protein. Analysis of this model reveals that formation of scaffold-kinase complexes can be used effectively to regulate the specificity, efficiency, and amplitude of signal propagation. In particular, for any generic scaffold there exists a concentration value optimal for signal amplitude. The location of the optimum is determined by the concentrations of the kinases rather than their binding constants and in this way is scaffold independent. This effect and the alteration of threshold properties of the signal propagation at high scaffold concentrations might alter local signaling properties at different subcellular compartments. Different scaffold levels and types might then confer specialized properties to tune evolutionarily conserved signaling modules to specific cellular contexts.
authors.affiliation: Division of Engineering and Applied Science and Division of Biology and Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA 91125, USA. andre@paradise.caltech.edu
authors.forename: A
authors.initials: A
authors.lastname: Levchenko
authors.forename: J
authors.initials: J
authors.lastname: Bruck
authors.forename: P W
authors.initials: PW
authors.lastname: Sternberg
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins / Q000502:physiology*; D003198:Computer Simulation; D004268:DNA-Binding Proteins / Q000502:physiology*; D004789:Enzyme Activation; D007700:Kinetics; D020935:MAP Kinase Signaling System; D046911:Macromolecular Substances; D008954:Models, Biological; D010766:Phosphorylation; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D014157:Transcription Factors / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C491779:Elf4 protein, mouse; C485425:LAMTOR3 protein, human; D046911:Macromolecular Substances; D014157:Transcription Factors