title: MEK1 and MEK2 differentially control the duration and amplitude of the ERK cascade response.
abstract: The Raf/MEK/ERK cascade is one of the most studied and important signal transduction pathways. However, existing models largely ignore the existence of isoforms of the constituent kinases and their interactions. Here, we propose a model of the ERK cascade that includes heretofore neglected differences between isoforms of MEK. In particular, MEK1 is subject to a negative feedback from activated ERK, which is further conferred to MEK2 via hetero-dimerization. Specifically, ERK phosphorylates MEK1 at the residue Thr292, hypothetically creating an additional phosphatase binding site, accelerating MEK1 and MEK2 dephosphorylation. We incorporated these recently discovered interactions into a mathematical model of the ERK cascade that reproduces the experimental results of Catalanotti et al (2009 Nature Struct. Mol. Biol. 16 294-303) and Kamioka et al (2010 J. Biol. Chem. 285 33540-8). Furthermore, the model allows for predictions regarding the differences in the catalytic activity and function of the MEK isoforms. We propose that the MEK1/MEK2 ratio regulates the duration of the response, which increases with the level of MEK2 and decreases with the level of MEK1. In turn, the amplitude of the response is controlled by the total amount of the two isoforms. We confirm the proposed model structure performing a random parameter sampling, which led us to the conclusion that the sampled parameters, selected to properly reproduce wild-type (WT) cell behavior, to allow for qualitative reproduction of differences in behavior WT cells and cell mutants studied experimentally.
authors.affiliation: Institute of Fundamental Technological Research, Polish Academy of Sciences, 02-106 Warsaw, Poland.
authors.forename: Pawel
authors.initials: P
authors.lastname: Kocieniewski
authors.forename: Tomasz
authors.initials: T
authors.lastname: Lipniacki
mesh_terms: D000818:Animals; D003198:Computer Simulation; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000378:metabolism*; D048370:MAP Kinase Kinase 2 / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D010766:Phosphorylation; D060066:Protein Interaction Maps; D020033:Protein Isoforms / Q000378:metabolism
chemical_list: D020033:Protein Isoforms; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2