Analyzing ERK 1/2 signalling and targets.
The ERK cascade (e.g. Raf-1) protects the heart from cell death and ischemic injury but can also turn maladaptive. Furthermore, an additional autophosphorylation of ERK2 at Thr188 (Erk1 at Thr208) allows ERK to phosphorylate nuclear targets involved in hypertrophy, stressing this additional phosphorylation as a promising pharmacological target. An in silico model was assembled and setup to reproduce different phosphorylation states of ERK 1/2 and various types of stimuli (hypertrophic versus non-hypertrophic). Synergistic and antagonistic receptor stimuli can be predicted in a semi-quantitative model, simulated time courses were experimentally validated. Furthermore, we detected new targets of ERK 1/2, which possibly contribute to the development of pathological hypertrophy. In addition we modeled further interaction partners involved in the protective and maladaptive cascade. Experimental validation included different gene expression data sets supporting key components and novel interaction partners as well as time courses in chronic heart failure.
Department of Bioinformatics, Biocenter, University of Würzburg, Würzburg, Germany. dandekar@biozentrum.uni-wuerzburg.de.
Alexandra
A
Brietz
Department of Bioinformatics, Biocenter, University of Würzburg, Würzburg, Germany. dandekar@biozentrum.uni-wuerzburg.de.
Kristin Verena
KV
Schuch
Department of Bioinformatics, Biocenter, University of Würzburg, Würzburg, Germany. dandekar@biozentrum.uni-wuerzburg.de.
Gaby
G
Wangorsch
Biomedizinsche Forschung, Leibniz Institut für Analytische Wissenschaften - ISAS - e.V, Bunsen-Kirchhoff Straße 11, 44139 Dortmund, Germany and West German Heart and Vascular Center Essen, University Hospital Essen-Duisburg, Duisburg, Germany.
Kristina
K
Lorenz
Department of Bioinformatics, Biocenter, University of Würzburg, Würzburg, Germany. dandekar@biozentrum.uni-wuerzburg.de.
Thomas
T
Dandekar
D000818:Animals; D002352:Carrier Proteins; D002460:Cell Line; D003198:Computer Simulation; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D010766:Phosphorylation; D011485:Protein Binding; D060066:Protein Interaction Maps; D015203:Reproducibility of Results
D002352:Carrier Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3