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Sasagawa (2005), MAPK

February 2007, model of the month by Lu Li
Original model: BIOMD0000000049

One paradox in signal transduction is how various signals could be integrated into a common signaling pathway, then promote distinct outcomes. One example is the Raf --> mitogen-activated protein kinase kinase (MEK) --> extracellular signal-regulated kinase (ERK) pathway. Two growth hormones, the epidermal growth factor (EGF) and the nerve growth factor (NGF), use this pathway to cause PC12 cell proliferation and differentiation, respectively [1]. Recent studies have set up the molecular framework based on this signaling pathway, trying to find answers for this fundamental question.

Early experimental studies have confirmed that the duration of ERK activation is the key to different responses to EGF and NGF signals [1]. Moreover, EGF induces the transient ERK activation, whereas NGF causes the transient and the sustained ERK activation [2,3,4]. However, the mechanisms of how the system captures the signal information and governs the dynamic behavior in downstream are still being debated.

Schematic overview of EGF and NGF dependent ERK signalling networks
Figure 1: Schematic overview of EGF and NGF dependent ERK signalling networks

To address this question, Sasagawa et al. [5] applied a computational modeling approach, combined with in vivo measurements on this pathway. As shown in figure 1, this is not a fully detailed model including every molecules involved in this signaling pathway. Instead, the author quickly linked EGF and NGF stimuli to downstream ERK through an abstract molecular framework. Every component and parameter included in this model was based on previous studies or assumptions. Most importantly, before the author moved to any important conclusion, he used the in vivo measurements to validate simulation results.

The first question Sasagawa et al. approached was how dynamic behavior of stimuli would influence ERK activation. Simulations were conducted, first based on constant stimuli with various concentrations, then on varying stimuli with different temporal rates. They found that the transient ERK activation depends on rapid temporal rate of EGF or NGF, whereas, the sustained ERK activation only depends on the final concentration of NGF but not on its temporal rate of change (Fig. 2) [5]. Interestingly, both in silico simulation and in vivo measurements indicated that Ras activation is transient in response to both stimuli; and Rap1 activation is transient after EGF stimulus, whereas sustained after NGF stimulus [5]. These results raised the second question the author addressed immediately – Are Ras and Rap1 the key molecules that transfer the temporal rates and final concentrations of growth factors to distinct ERK activation, and how?

Distinct dynamics of transient and sustained ERK activation
Figure 2: Distinct dynamics of transient and sustained ERK activation. For epidermal growth factor (EGF, a) and nerve growth factor (NGF, b). The constant and increasing stimuli, and the corresponding responses are indicated by solid and dashed lines, respectively.

According to their small Ras, Rap1 models (Fig. 3), Sasagawa et al. concluded that the Ras and the Rap1 systems capture the temporal rate and final concentration of growth factors via the transient Ras activation, and the transient and the sustained Rap1 activation, then encode into dynamic ERK activation. The growth-factor-dependent fast SOS and the slow Ras-GAP activation are requirements for the transient Ras activation which captures the changing rate of growth factors and leads to the transient ERK activation. On the other hand, the growth-factor-dependent C3G activation and the constant Rap1-GAP activity are two important components for the sustained Rap1 activation. In addition, the distinct affinities of the fibroblast growth factor receptor substrate 2 (FRS2) to both receptors (EGFR and TrkA) are responsible for distinct responses of Rap1 to different stimuli [5].

To summarise, this model shows that although the EGF- and the NGF- dependent ERK activation pathways are integrated from the downstream of the same pathway to ERK, because of different dynamics from the upstream, they promote distinct ERK activation. Thus, differentiation and proliferation may involve a balance among MAPK signaling pathways that depends not only on the combination of cellular stimuli, but also on the upstream of adaptor proteins, such as small GTPases.

The distinct temporal dynamics of transient and sustained ERK activation via Ras and Rap1 activation
Figure 3: The distinct temporal dynamics of transient and sustained ERK activation via Ras and Rap1 activation

Related Models in BioModels Database

  1. BIOMD0000000033: Brown2004_NGF_EGF_signaling
  2. BIOMD0000000048: Kholodenko1999_EGFRsignaling

Bibliographic References

  1. D. Vaudry, P.J. Stork, P. Lazarovici, and L.E. Eiden. Signaling pathways for PC12 cell differentiation: making the right connections. Science, 296:1648−1649, 2002. [SRS@EBI]
  2. Y. Gotoh, E. Nishida, T. Yamashita, M. Hoshi, M. Kawakami, and H. Sakai. Microtubule-associated-protein (MAP) kinase activated by nerve growth factor and epidermal growth factor in PC12 cells. Identity with the mitogen-activated MAP kinase of fibroblastic cells. Eur. J. Biochem., 193:661−669, 1990. [SRS@EBI]
  3. M.S. Qui and S.H. Green. PC12 cell neuronal differentiation is associated with prolonged p21ras activity and consequent prolonged ERK activity. Neuron, 9:705−717, 1992. [SRS@EBI]
  4. S. Traverse, N. Gomez, H. Paterson, C. Marshall, and P. Cohen. Sustained activation of the mitogen-activated protein (MAP) kinase cascade may be required for differentiation of PC12 cells. Comparison of the effects of nerve growth factor and epidermal growth factor. Biochem. J., 288:351−355, 1992. [SRS@EBI]
  5. S. Sasagawa, Y. Ozaki, K. Fuijita, S. Kuroda. Prediction and validation of the distince dynamics of transient and sustained ERK activation. Nature Cell Biology, 7(4):365-372, 2005.[SRS@EBI]