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Topological analysis of MAPK cascade for kinetic ErbB signaling.

Nakakuki T, Yumoto N, Naka T, Shirouzu M, Yokoyama S, Hatakeyama M - PLoS ONE (2008)

Bottom Line: Ligand-induced homo- and hetero-dimer formation of ErbB receptors results in different biological outcomes irrespective of recruitment and activation of similar effector proteins.We found that the pathway structure is characterized by ERK-mediated positive feedback regulation of B-Raf and B-Raf-mediated negative regulation of Raf-1.From a sensitivity analysis of the detailed upstream model for Ras activation, we concluded that Ras activation dynamics is dominated by heterodimer-mediated signaling coordination with a large initial speed of dimerization when the concentration of the ErbB4 receptor is considerably high.

View Article: PubMed Central - PubMed

Affiliation: Cellular Systems Biology Team, Computational and Experimental Systems Biology Group, RIKEN Genomic Sciences Center, Tsurumi-ku, Yokohama, Kanagawa, Japan.

ABSTRACT
Ligand-induced homo- and hetero-dimer formation of ErbB receptors results in different biological outcomes irrespective of recruitment and activation of similar effector proteins. Earlier experimental research indicated that cells expressing both EGFR (epidermal growth factor receptor) and the ErbB4 receptor (E1/4 cells) induced E1/4 cell-specific B-Raf activation and higher extracellular signal-regulated kinase (ERK) activation, followed by cellular transformation, than cells solely expressing EGFR (E1 cells) in Chinese hamster ovary (CHO) cells. Since our experimental data revealed the presence of positive feedback by ERK on upstream pathways, it was estimated that the cross-talk/feedback pathway structure of the Raf-MEK-ERK cascade might affect ERK activation dynamics in our cell system. To uncover the regulatory mechanism concerning the ERK dynamics, we used topological models and performed parameter estimation for all candidate structures that possessed ERK-mediated positive feedback regulation of Raf. The structure that reliably reproduced a series of experimental data regarding signal amplitude and duration of the signaling molecules was selected as a solution. We found that the pathway structure is characterized by ERK-mediated positive feedback regulation of B-Raf and B-Raf-mediated negative regulation of Raf-1. Steady-state analysis of the estimated structure indicated that the amplitude of Ras activity might critically affect ERK activity through ERK-B-Raf positive feedback coordination with sustained B-Raf activation in E1/4 cells. However, Rap1 that positively regulates B-Raf activity might be less effective concerning ERK and B-Raf activity. Furthermore, we investigated how such Ras activity in E1/4 cells can be regulated by EGFR/ErbB4 heterodimer-mediated signaling. From a sensitivity analysis of the detailed upstream model for Ras activation, we concluded that Ras activation dynamics is dominated by heterodimer-mediated signaling coordination with a large initial speed of dimerization when the concentration of the ErbB4 receptor is considerably high. Such characteristics of the signaling cause the preferential binding of the Grb2-SOS complex to heterodimer-mediated signaling molecules.

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Effect of ErbB4 receptor concentration on the time-course pattern.The concentration of the ErbB4 receptor (E4) was changed from 100% of the total ErbB4 receptors (E4 = 1.0) in E1/4 cells to 0% (E4 = 0.0). Figures demonstrate time-course patterns of signaling molecules in relation to the abundance of the ErbB4 receptor in silico. (A) and (C) The signaling molecules E11P_ShcP and E11P_ShcP_GS in EGFR homodimer-mediated pathways, respectively. (B) and (D) The signaling molecules E14P_ShcP and E14P_ShcP_GS in EGFR/ErbB4 heterodimer-mediated pathways, respectively. The colors of the graphs indicate activity (% of total protein).
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pone-0001782-g009: Effect of ErbB4 receptor concentration on the time-course pattern.The concentration of the ErbB4 receptor (E4) was changed from 100% of the total ErbB4 receptors (E4 = 1.0) in E1/4 cells to 0% (E4 = 0.0). Figures demonstrate time-course patterns of signaling molecules in relation to the abundance of the ErbB4 receptor in silico. (A) and (C) The signaling molecules E11P_ShcP and E11P_ShcP_GS in EGFR homodimer-mediated pathways, respectively. (B) and (D) The signaling molecules E14P_ShcP and E14P_ShcP_GS in EGFR/ErbB4 heterodimer-mediated pathways, respectively. The colors of the graphs indicate activity (% of total protein).

Mentions: Next, we investigated the effect of ErbB4 receptor-mediated pathways on Ras activation. To this end, we varied the concentration of the ErbB4 receptor from about 100% of the total ErbB4 receptors in E1/4 cells to about 0% (Figures 8 and 9). The model with 0% ErbB4 receptors corresponds to the E1 cell model. As the abundance of ErbB4 receptors increased, the peak level of activation of E14P_ShcP_GS increased with a steep slope, whereas that of E11P_ShcP_GS decreased (Figure 8). Furthermore, we found that the peak level of E14P_ShcP_GS was much greater than that of E11P_ShcP_GS, especially for higher concentrations of the ErbB4 receptor. Therefore, the peak level of Ras activation might be critically affected by the concentration of ErbB4 receptors through E14P_ShcP_GS (step 22 in Figure 6) rather than E11P_ShcP_GS (step12). Figure 9 shows the time-course patterns of signaling molecules in this sensitivity analysis. The change in peak level of E14P_ShcP was also affected by the concentration of ErbB4 receptors as well as E14P_ShcP_GS (Figures 9B and 9D), although E11P_ShcP was not sensitive to such changes (Figures 9A). However, the peak level of E11P_ShcP_GS became quite small at around a 100% concentration of ErbB4 receptors despite such insensitivity (Figure 9C) compared to that of E14P_ShcP_GS (Figure 9D). E11P_ShcP and E14P_ShcP share the interaction partner, the GS (Grb2-SOS) complex. In addition, the initial reaction velocity of E14P_ShcP was faster than that of E11P_ShcP at higher concentrations of the ErbB4 receptor (60–100%) (Figures 9A and 9B). Therefore, GS might preferentially bind to E14P_ShcP rather than E11P_ShcP. These results as a whole indicate that the concentration of the ErbB4 receptor in our detailed model might be quite important for the considerably strong Ras activation observed in E1/4 cells, where the ErbB4 receptor-mediated signaling pathway can dominate Ras activation dynamics.


Topological analysis of MAPK cascade for kinetic ErbB signaling.

Nakakuki T, Yumoto N, Naka T, Shirouzu M, Yokoyama S, Hatakeyama M - PLoS ONE (2008)

Effect of ErbB4 receptor concentration on the time-course pattern.The concentration of the ErbB4 receptor (E4) was changed from 100% of the total ErbB4 receptors (E4 = 1.0) in E1/4 cells to 0% (E4 = 0.0). Figures demonstrate time-course patterns of signaling molecules in relation to the abundance of the ErbB4 receptor in silico. (A) and (C) The signaling molecules E11P_ShcP and E11P_ShcP_GS in EGFR homodimer-mediated pathways, respectively. (B) and (D) The signaling molecules E14P_ShcP and E14P_ShcP_GS in EGFR/ErbB4 heterodimer-mediated pathways, respectively. The colors of the graphs indicate activity (% of total protein).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2262155&req=5

pone-0001782-g009: Effect of ErbB4 receptor concentration on the time-course pattern.The concentration of the ErbB4 receptor (E4) was changed from 100% of the total ErbB4 receptors (E4 = 1.0) in E1/4 cells to 0% (E4 = 0.0). Figures demonstrate time-course patterns of signaling molecules in relation to the abundance of the ErbB4 receptor in silico. (A) and (C) The signaling molecules E11P_ShcP and E11P_ShcP_GS in EGFR homodimer-mediated pathways, respectively. (B) and (D) The signaling molecules E14P_ShcP and E14P_ShcP_GS in EGFR/ErbB4 heterodimer-mediated pathways, respectively. The colors of the graphs indicate activity (% of total protein).
Mentions: Next, we investigated the effect of ErbB4 receptor-mediated pathways on Ras activation. To this end, we varied the concentration of the ErbB4 receptor from about 100% of the total ErbB4 receptors in E1/4 cells to about 0% (Figures 8 and 9). The model with 0% ErbB4 receptors corresponds to the E1 cell model. As the abundance of ErbB4 receptors increased, the peak level of activation of E14P_ShcP_GS increased with a steep slope, whereas that of E11P_ShcP_GS decreased (Figure 8). Furthermore, we found that the peak level of E14P_ShcP_GS was much greater than that of E11P_ShcP_GS, especially for higher concentrations of the ErbB4 receptor. Therefore, the peak level of Ras activation might be critically affected by the concentration of ErbB4 receptors through E14P_ShcP_GS (step 22 in Figure 6) rather than E11P_ShcP_GS (step12). Figure 9 shows the time-course patterns of signaling molecules in this sensitivity analysis. The change in peak level of E14P_ShcP was also affected by the concentration of ErbB4 receptors as well as E14P_ShcP_GS (Figures 9B and 9D), although E11P_ShcP was not sensitive to such changes (Figures 9A). However, the peak level of E11P_ShcP_GS became quite small at around a 100% concentration of ErbB4 receptors despite such insensitivity (Figure 9C) compared to that of E14P_ShcP_GS (Figure 9D). E11P_ShcP and E14P_ShcP share the interaction partner, the GS (Grb2-SOS) complex. In addition, the initial reaction velocity of E14P_ShcP was faster than that of E11P_ShcP at higher concentrations of the ErbB4 receptor (60–100%) (Figures 9A and 9B). Therefore, GS might preferentially bind to E14P_ShcP rather than E11P_ShcP. These results as a whole indicate that the concentration of the ErbB4 receptor in our detailed model might be quite important for the considerably strong Ras activation observed in E1/4 cells, where the ErbB4 receptor-mediated signaling pathway can dominate Ras activation dynamics.

Bottom Line: Ligand-induced homo- and hetero-dimer formation of ErbB receptors results in different biological outcomes irrespective of recruitment and activation of similar effector proteins.We found that the pathway structure is characterized by ERK-mediated positive feedback regulation of B-Raf and B-Raf-mediated negative regulation of Raf-1.From a sensitivity analysis of the detailed upstream model for Ras activation, we concluded that Ras activation dynamics is dominated by heterodimer-mediated signaling coordination with a large initial speed of dimerization when the concentration of the ErbB4 receptor is considerably high.

View Article: PubMed Central - PubMed

Affiliation: Cellular Systems Biology Team, Computational and Experimental Systems Biology Group, RIKEN Genomic Sciences Center, Tsurumi-ku, Yokohama, Kanagawa, Japan.

ABSTRACT
Ligand-induced homo- and hetero-dimer formation of ErbB receptors results in different biological outcomes irrespective of recruitment and activation of similar effector proteins. Earlier experimental research indicated that cells expressing both EGFR (epidermal growth factor receptor) and the ErbB4 receptor (E1/4 cells) induced E1/4 cell-specific B-Raf activation and higher extracellular signal-regulated kinase (ERK) activation, followed by cellular transformation, than cells solely expressing EGFR (E1 cells) in Chinese hamster ovary (CHO) cells. Since our experimental data revealed the presence of positive feedback by ERK on upstream pathways, it was estimated that the cross-talk/feedback pathway structure of the Raf-MEK-ERK cascade might affect ERK activation dynamics in our cell system. To uncover the regulatory mechanism concerning the ERK dynamics, we used topological models and performed parameter estimation for all candidate structures that possessed ERK-mediated positive feedback regulation of Raf. The structure that reliably reproduced a series of experimental data regarding signal amplitude and duration of the signaling molecules was selected as a solution. We found that the pathway structure is characterized by ERK-mediated positive feedback regulation of B-Raf and B-Raf-mediated negative regulation of Raf-1. Steady-state analysis of the estimated structure indicated that the amplitude of Ras activity might critically affect ERK activity through ERK-B-Raf positive feedback coordination with sustained B-Raf activation in E1/4 cells. However, Rap1 that positively regulates B-Raf activity might be less effective concerning ERK and B-Raf activity. Furthermore, we investigated how such Ras activity in E1/4 cells can be regulated by EGFR/ErbB4 heterodimer-mediated signaling. From a sensitivity analysis of the detailed upstream model for Ras activation, we concluded that Ras activation dynamics is dominated by heterodimer-mediated signaling coordination with a large initial speed of dimerization when the concentration of the ErbB4 receptor is considerably high. Such characteristics of the signaling cause the preferential binding of the Grb2-SOS complex to heterodimer-mediated signaling molecules.

Show MeSH
Related in: MedlinePlus