Freiburg Institute for Advanced Studies, LifeNet, Albert-Ludwigs-University of Freiburg, Albertstrasse 19, Freiburg, Germany.
Bioinformatics. 2012 Sep 15;28(18):i495-i501. doi: 10.1093/bioinformatics/bts410.
Cell migration is a complex process that is controlled through the time-sequential feedback regulation of protein signalling and gene regulation. Based on prior knowledge and own experimental data, we developed a large-scale dynamic network describing the onset and maintenance of hepatocyte growth factor-induced migration of primary human keratinocytes. We applied Boolean logic to capture the qualitative behaviour as well as short-and long-term dynamics of the complex signalling network involved in this process, comprising protein signalling, gene regulation and autocrine feedback.
A Boolean model has been compiled from time-resolved transcriptome data and literature mining, incorporating the main pathways involved in migration from initial stimulation to phenotype progress. Steady-state analysis under different inhibition and stimulation conditions of known key molecules reproduces existing data and predicts novel interactions based on our own experiments. Model simulations highlight for the first time the necessity of a temporal sequence of initial, transient MET receptor (met proto-oncogene, hepatocyte growth factor receptor) and subsequent, continuous epidermal growth factor/integrin signalling to trigger and sustain migration by autocrine signalling that is integrated through the Focal adhesion kinase protein. We predicted in silico and verified in vitro that long-term cell migration is stopped if any of the two feedback loops are inhibited.
The network file for analysis with the R BoolNet library is available in the Supplementary Information.
melanie.boerries@frias.uni-freiburg.de or hauke.busch@frias.uni-freiburg.de
Supplementary data are available at Bioinformatics online.
细胞迁移是一个复杂的过程，通过蛋白质信号的时间顺序反馈调节和基因调控来控制。基于先前的知识和自己的实验数据，我们开发了一个大规模的动态网络，描述了人原代角质形成细胞中肝细胞生长因子诱导迁移的起始和维持。我们应用布尔逻辑来捕捉涉及该过程的复杂信号网络的定性行为以及短期和长期动力学，包括蛋白质信号、基因调控和自分泌反馈。
从时间分辨的转录组数据和文献挖掘中编译了一个布尔模型，其中包含了从初始刺激到表型进展过程中迁移所涉及的主要途径。在已知关键分子的不同抑制和刺激条件下的稳态分析再现了现有数据，并根据我们自己的实验预测了新的相互作用。模型模拟首次强调了初始、瞬态 MET 受体（met 原癌基因、肝细胞生长因子受体）和随后的、连续的表皮生长因子/整合素信号触发和维持迁移的时间序列的必要性，这种自分泌信号通过粘着斑激酶蛋白进行整合。我们预测并在体外验证了，如果两个反馈回路中的任何一个被抑制，长期细胞迁移就会停止。
可用于 R BoolNet 库分析的网络文件可在补充信息中获得。
melanie.boerries@frias.uni-freiburg.de 或 hauke.busch@frias.uni-freiburg.de
补充数据可在生物信息学在线获得。
