Systematic approach for the analysis of signal transduction pathways: combination of simulation and experiment

Multiple signal transduction pathways regulate various cellular processes. Due to a complex nature of signal transduction pathways, it is intuitively difficult to understand the systematic relationship between signaling molecule and cellular processes. To address this issue, it is necessary to utilize the conceptual framework of computational simulation. We have conducted kinetic simulation study of signal transduction pathways underlying cerebellar long-term depression (LTD), a possible cellular basis of cerebellar learning, and myosin phosphorylation, a key reaction of regulation of cell morphology, based on the biochemical parameters experimentally obtained. We found that the signal transduction pathways currently known can reproduce some, but not all of the experimental results, predicting an existence of a missing pathway(s) in both signal transduction pathways; requirement of additional pathway(s) for initial phase of cerebellar LTD and for prolonged phase of myosin phosphorylation. By taking advantage of the kinetic simulation, we predicted that the prolonged phosphorylation of myosin phosphatase should be responsible for the prolonged phase of myosin phosphorylation, which was not reproduced by the current signal transduction pathways. We are currently trying to test this theoretical prediction.

One of the features of signal transduction is that the same or similar signal pathways are often utilized in many distinct cellular processes. Thus, it is quite useful to build each signaling pathway as a general module. We are also trying to build these modules so that we can apply modules to any cellular processes.

Thus, a novel systematic approach using experiments together with kinetic simulation greatly improve our understanding the behavior of complex signal transduction pathways and is a powerful tool for predicting a missing pathways which is difficult to be found by individual experiments. Our goal is to clarify and understand the whole mechanisms of various cellular processes by use of the novel systematic approach.