Random Parameter Sampling of a Generic Three-Tier MAPK Cascade Model Reveals Major Factors Affecting Its Versatile Dynamics

The mitogen-activated protein kinase (MAPK) pathway is considered to be a central block in many biological signaling networks. Despite the common core cascade structure, the activation of MAPK in different biological systems can exhibit different types of dynamic behaviors. Computer modeling may help to reveal the mechanisms underlying such variations. However, so far most computational models of the MAPK cascade have been system-specific, or to reflect a particular type among the wide spectrum of possible dynamics. To obtain a general and integrated view of the relationship between the dynamics of MAPK activation and the structures and parameters of the MAPK cascade, we constructed a generic model by comparing previous models covering different specific biological systems. We assumed that reliable qualitative results could be predicted through a qualitative model with pseudo parameters. We used randomly sampled parameters instead of a specific set of “best-fit” parameters to avoid biases towards any particular systems. A range of dynamics behaviors for MAPK activation, including ultrasensitivity, bistability, transient activation and oscillation, were successfully predicted by the generic model. The results indicated that the steady state dynamics (ultrasensitivity and bistability) was jointly determined by the three-tiered structure of the MAPK cascade and the competitive substrate binding in the dual-phosphorylation processes of the central components, while the temporal dynamics (transient activation and oscillation) was mainly affected by the upstream signaling pathway and feedbacks. Moreover, MAPK kinase (MAPKK) played more important roles than the other two components in determining the dynamics of MAPK activation. We hypothesize that this is an important and advantageous property for the regulation and for the functional diversity of MAPK pathways in real cells. Finally, to assist developing generic models for signaling motifs through model comparisons, we proposed a reaction-based database to make the model data more flexible and interoperable.

丝裂原活化蛋白激酶（mitogen-activated protein kinase, MAPK）通路被视为众多生物信号网络中的核心枢纽模块。尽管这类通路普遍拥有保守的核心级联结构，但不同生物系统中MAPK的激活过程却可表现出多样的动态行为特征。计算机建模有助于揭示这类差异背后的分子机制。然而迄今为止，绝大多数针对MAPK级联反应的计算模型均为系统特异性模型，或是仅能反映广泛潜在动态谱中的某一类特定行为。为了全面且整合地理解MAPK激活动态与MAPK级联反应结构及参数之间的关联，本研究通过比对不同特定生物系统的已有模型，构建了一个通用化模型。本研究假设，使用伪参数构建的定性模型即可预测可靠的定性结果。为避免偏向特定系统，研究中采用随机采样得到的参数集，而非特定的“最优拟合”参数集。该通用模型成功预测了MAPK激活的多种动态行为，包括超敏性、双稳态、瞬时激活与振荡现象。研究结果显示，稳态动态（超敏性与双稳态）由MAPK级联的三级结构与核心组分双重磷酸化过程中的底物竞争性结合共同决定，而时序动态（瞬时激活与振荡）则主要受上游信号通路及反馈调控的影响。此外，MAPK激酶（MAPKK）相较于另外两个组分发挥了更为关键的作用。本研究推测，这一特性对于真实细胞中MAPK通路的调控及功能多样性而言，是一项重要且具备优势的特征。最后，为助力通过模型比对构建信号基序的通用模型，本研究提出了一个基于反应的数据库，以提升模型数据的灵活性与互操作性。