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Integration of a phosphatase cascade with the mitogen-activated protein kinase pathway provides for a novel signal processing function.

Chaudhri VK, Kumar D, Misra M, Dua R, Rao KV - J. Biol. Chem. (2009)

Bottom Line: Activation induced the alignment of a phosphatase cascade in parallel with the MAPK pathway.Shifts in this balance yielded modulations in topology of the motif, thereby expanding the repertoire of output responses.Thus, we identify an added dimension to signal processing wherein the output response to an external stimulus is additionally filtered through indicators that define the phenotypic status of the cell.

View Article: PubMed Central - PubMed

Affiliation: Immunology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110067, India.

ABSTRACT
We mathematically modeled the receptor-dependent mitogen-activated protein kinase (MAPK) signaling by incorporating the regulation through cellular phosphatases. Activation induced the alignment of a phosphatase cascade in parallel with the MAPK pathway. A novel regulatory motif was, thus, generated, providing for the combinatorial control of each MAPK intermediate. This ensured a non-linear mode of signal transmission with the output being shaped by the balance between the strength of input signal and the activity gradient along the phosphatase axis. Shifts in this balance yielded modulations in topology of the motif, thereby expanding the repertoire of output responses. Thus, we identify an added dimension to signal processing wherein the output response to an external stimulus is additionally filtered through indicators that define the phenotypic status of the cell.

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Phosphatase-mediated regulation of the MAPK signaling response. The influence of individual phosphatases in sensitizing the ERK output was monitored in silico by analyzing ligand dose versus peak phospho-ERK (ppERK) levels within the first 30 min of activation. This analysis was performed either in normal cells (Normal) or in cells where the indicated phosphatase was depleted from the system. In each case, the -fold change in ligand concentration required to increase ERK phosphorylation from 10 to 90% of its maximal value is also given (F). These values confirm that the ERK response remains proportional under all of these conditions.
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Figure 5: Phosphatase-mediated regulation of the MAPK signaling response. The influence of individual phosphatases in sensitizing the ERK output was monitored in silico by analyzing ligand dose versus peak phospho-ERK (ppERK) levels within the first 30 min of activation. This analysis was performed either in normal cells (Normal) or in cells where the indicated phosphatase was depleted from the system. In each case, the -fold change in ligand concentration required to increase ERK phosphorylation from 10 to 90% of its maximal value is also given (F). These values confirm that the ERK response remains proportional under all of these conditions.

Mentions: We first examined how the connected network of phosphatases influenced signal output from the MAPK module. This was achieved through in silico experiments examining the ligand dose dependence of ERK phosphorylation under conditions where the individual phosphatases were depleted one at a time. Fig. 5 shows the results of these experiments where Normal depicts the profile obtained in the unperturbed condition. It is evident that, with the exception of PP1, no other phosphatase depletion had any significant effect on the proportional nature of ERK activation (Fig. 5). The observed effect of PP1 depletion is consistent with our earlier experimental findings involving depletion of this enzyme by siRNA. In these experiments a marked decrease in the magnitude of ERK activation was obtained at the later time points (22). Thus, these results suggest that PP1 may play an important role in buffering the inactive pool of hyperphosphorylated Raf, which is generated by activated ERK through a positive feedback loop, and Akt (19, 47, 48).


Integration of a phosphatase cascade with the mitogen-activated protein kinase pathway provides for a novel signal processing function.

Chaudhri VK, Kumar D, Misra M, Dua R, Rao KV - J. Biol. Chem. (2009)

Phosphatase-mediated regulation of the MAPK signaling response. The influence of individual phosphatases in sensitizing the ERK output was monitored in silico by analyzing ligand dose versus peak phospho-ERK (ppERK) levels within the first 30 min of activation. This analysis was performed either in normal cells (Normal) or in cells where the indicated phosphatase was depleted from the system. In each case, the -fold change in ligand concentration required to increase ERK phosphorylation from 10 to 90% of its maximal value is also given (F). These values confirm that the ERK response remains proportional under all of these conditions.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2801257&req=5

Figure 5: Phosphatase-mediated regulation of the MAPK signaling response. The influence of individual phosphatases in sensitizing the ERK output was monitored in silico by analyzing ligand dose versus peak phospho-ERK (ppERK) levels within the first 30 min of activation. This analysis was performed either in normal cells (Normal) or in cells where the indicated phosphatase was depleted from the system. In each case, the -fold change in ligand concentration required to increase ERK phosphorylation from 10 to 90% of its maximal value is also given (F). These values confirm that the ERK response remains proportional under all of these conditions.
Mentions: We first examined how the connected network of phosphatases influenced signal output from the MAPK module. This was achieved through in silico experiments examining the ligand dose dependence of ERK phosphorylation under conditions where the individual phosphatases were depleted one at a time. Fig. 5 shows the results of these experiments where Normal depicts the profile obtained in the unperturbed condition. It is evident that, with the exception of PP1, no other phosphatase depletion had any significant effect on the proportional nature of ERK activation (Fig. 5). The observed effect of PP1 depletion is consistent with our earlier experimental findings involving depletion of this enzyme by siRNA. In these experiments a marked decrease in the magnitude of ERK activation was obtained at the later time points (22). Thus, these results suggest that PP1 may play an important role in buffering the inactive pool of hyperphosphorylated Raf, which is generated by activated ERK through a positive feedback loop, and Akt (19, 47, 48).

Bottom Line: Activation induced the alignment of a phosphatase cascade in parallel with the MAPK pathway.Shifts in this balance yielded modulations in topology of the motif, thereby expanding the repertoire of output responses.Thus, we identify an added dimension to signal processing wherein the output response to an external stimulus is additionally filtered through indicators that define the phenotypic status of the cell.

View Article: PubMed Central - PubMed

Affiliation: Immunology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110067, India.

ABSTRACT
We mathematically modeled the receptor-dependent mitogen-activated protein kinase (MAPK) signaling by incorporating the regulation through cellular phosphatases. Activation induced the alignment of a phosphatase cascade in parallel with the MAPK pathway. A novel regulatory motif was, thus, generated, providing for the combinatorial control of each MAPK intermediate. This ensured a non-linear mode of signal transmission with the output being shaped by the balance between the strength of input signal and the activity gradient along the phosphatase axis. Shifts in this balance yielded modulations in topology of the motif, thereby expanding the repertoire of output responses. Thus, we identify an added dimension to signal processing wherein the output response to an external stimulus is additionally filtered through indicators that define the phenotypic status of the cell.

Show MeSH
Related in: MedlinePlus