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

Zhongxing Mai,Haiyan Liu,William W Lytton

doi:10.1371/journal.pone.0054441

Abstract

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.

Highlights

The mitogen-activated protein kinase (MAPK) cascade is a central block in many cell signaling networks
The activation of a MAPK generally involves two subpathways: an upstream sub-pathway that lead to the activation of a MAPK kinase (MAPKK) kinase (MAPKKK), and the central MAPK cascade that lead to the activation of a MAPK
The result indicated that the model including a positive feedback from active MAPK to B-Raf (MAPKKK activated by ErbB4) and an inhibitory link from active B-Raf to active Raf-1 (MAPKKK activated by EGFR) could best fit the experiment data [28]

Summary

Introduction

The mitogen-activated protein kinase (MAPK) cascade is a central block in many cell signaling networks. This cascade presents widely in cell signaling pathways associated with proliferation, differentiation and apoptosis [1,2,3]. MAPKs are a family of cellular kinases. When activated, they activate a number of downstream substrates that regulate transcription and translation [4,5]. The activation of a MAPK generally involves two subpathways: an upstream sub-pathway (e.g. the growth factor pathway [6] or the tumor necrosis factor pathway [7]) that lead to the activation of a MAPKK kinase (MAPKKK), and the central MAPK cascade that lead to the activation of a MAPK. The central MAPK cascade has the following three-tiered core structure [8]:

Methods

Results

Discussion

Conclusion