Brietz Alexandra, Schuch Kristin Verena, Wangorsch Gaby, Lorenz Kristina, Dandekar Thomas
Department of Bioinformatics, Biocenter, University of Würzburg, Würzburg, Germany.
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.
Mol Biosyst. 2016 Jul 19;12(8):2436-46. doi: 10.1039/c6mb00255b.
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.
ERK 信号级联反应（如Raf-1）可保护心脏免受细胞死亡和缺血性损伤，但也可能转变为适应不良。此外，ERK2在苏氨酸188（Erk1在苏氨酸208）处的额外自磷酸化使ERK能够磷酸化参与肥大的核靶点，强调这种额外的磷酸化是一个有前景的药理学靶点。构建并设置了一个计算机模型，以重现ERK 1/2的不同磷酸化状态和各种类型的刺激（肥大性与非肥大性）。在一个半定量模型中可以预测协同和拮抗受体刺激，模拟的时间进程得到了实验验证。此外，我们检测到了ERK 1/2的新靶点，它们可能促成病理性肥大的发展。此外，我们对参与保护和适应不良级联反应的其他相互作用伙伴进行了建模。实验验证包括支持关键成分和新型相互作用伙伴的不同基因表达数据集以及慢性心力衰竭中的时间进程。
