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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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Experimental confirmation of the systems properties of the MAPK-associated regulatory module. Panel A depicts peak MEK and ERK phosphorylation (10 min of stimulation with anti-IgG) levels obtained as a function of changes either in MKP3 or PP2A concentrations as described in the text. For the profiles obtained in silico (Predicted), the concentration ranges utilized is described in supplemental Fig. S8, whereas the extent of variation in phosphatase concentration/activity obtained experimentally (Experimental) is described under “Experimental Support for Signal Processing Function of Phosphatase Cascade.” The anti-IgG concentrations employed for the experiment in high ligand dose (upper panel) were 10 (blue line) and 25 (red line) μg/ml, whereas for low ligand dose (lower panel), it was 0.05 (blue line) and 0.5 (red line) μg/ml. OA, okadaic acid. Panel B describes the effects of combined variations in levels/activities of both MKP3 and PP2A on the magnitude of ERK phosphorylation. Here again, a comparison between the in silico (Predicted) and the experimentally (Experimental) obtained results is shown. Although a similarity in profiles between the two groups is clearly evident, the absence of a higher degree of concordance was primarily due to the limited number of data points in the experimental group. As described in the text, MKP3 levels were varied in the experimental sets either through specific depletion by siRNA (KD) or by overexpression (OE).
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Figure 8: Experimental confirmation of the systems properties of the MAPK-associated regulatory module. Panel A depicts peak MEK and ERK phosphorylation (10 min of stimulation with anti-IgG) levels obtained as a function of changes either in MKP3 or PP2A concentrations as described in the text. For the profiles obtained in silico (Predicted), the concentration ranges utilized is described in supplemental Fig. S8, whereas the extent of variation in phosphatase concentration/activity obtained experimentally (Experimental) is described under “Experimental Support for Signal Processing Function of Phosphatase Cascade.” The anti-IgG concentrations employed for the experiment in high ligand dose (upper panel) were 10 (blue line) and 25 (red line) μg/ml, whereas for low ligand dose (lower panel), it was 0.05 (blue line) and 0.5 (red line) μg/ml. OA, okadaic acid. Panel B describes the effects of combined variations in levels/activities of both MKP3 and PP2A on the magnitude of ERK phosphorylation. Here again, a comparison between the in silico (Predicted) and the experimentally (Experimental) obtained results is shown. Although a similarity in profiles between the two groups is clearly evident, the absence of a higher degree of concordance was primarily due to the limited number of data points in the experimental group. As described in the text, MKP3 levels were varied in the experimental sets either through specific depletion by siRNA (KD) or by overexpression (OE).

Mentions: As shown in supplemental Fig. S6, whereas inhibition of PP2A activity led to a linear increase in ERK phosphorylation, that of MEK displayed a bimodal response to PP2A (see also Fig. 8A). The sensitivity of ERK to PP2A activity likely derives from the concomitant decrease in the size of the pool of non-phosphorylated MKP3 as a result of decreasing PP2A levels. As discussed earlier, this would decrease the efficiency of MKP3-dependent dephosphorylation of ERK. In addition to this, however, a diminished pool of phospho-MKP3 would also imply a consequent reduction in the negative regulation of MKP1 and, thereby, an increase in the MKP1-dependent inactivation of ERK.


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)

Experimental confirmation of the systems properties of the MAPK-associated regulatory module. Panel A depicts peak MEK and ERK phosphorylation (10 min of stimulation with anti-IgG) levels obtained as a function of changes either in MKP3 or PP2A concentrations as described in the text. For the profiles obtained in silico (Predicted), the concentration ranges utilized is described in supplemental Fig. S8, whereas the extent of variation in phosphatase concentration/activity obtained experimentally (Experimental) is described under “Experimental Support for Signal Processing Function of Phosphatase Cascade.” The anti-IgG concentrations employed for the experiment in high ligand dose (upper panel) were 10 (blue line) and 25 (red line) μg/ml, whereas for low ligand dose (lower panel), it was 0.05 (blue line) and 0.5 (red line) μg/ml. OA, okadaic acid. Panel B describes the effects of combined variations in levels/activities of both MKP3 and PP2A on the magnitude of ERK phosphorylation. Here again, a comparison between the in silico (Predicted) and the experimentally (Experimental) obtained results is shown. Although a similarity in profiles between the two groups is clearly evident, the absence of a higher degree of concordance was primarily due to the limited number of data points in the experimental group. As described in the text, MKP3 levels were varied in the experimental sets either through specific depletion by siRNA (KD) or by overexpression (OE).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 8: Experimental confirmation of the systems properties of the MAPK-associated regulatory module. Panel A depicts peak MEK and ERK phosphorylation (10 min of stimulation with anti-IgG) levels obtained as a function of changes either in MKP3 or PP2A concentrations as described in the text. For the profiles obtained in silico (Predicted), the concentration ranges utilized is described in supplemental Fig. S8, whereas the extent of variation in phosphatase concentration/activity obtained experimentally (Experimental) is described under “Experimental Support for Signal Processing Function of Phosphatase Cascade.” The anti-IgG concentrations employed for the experiment in high ligand dose (upper panel) were 10 (blue line) and 25 (red line) μg/ml, whereas for low ligand dose (lower panel), it was 0.05 (blue line) and 0.5 (red line) μg/ml. OA, okadaic acid. Panel B describes the effects of combined variations in levels/activities of both MKP3 and PP2A on the magnitude of ERK phosphorylation. Here again, a comparison between the in silico (Predicted) and the experimentally (Experimental) obtained results is shown. Although a similarity in profiles between the two groups is clearly evident, the absence of a higher degree of concordance was primarily due to the limited number of data points in the experimental group. As described in the text, MKP3 levels were varied in the experimental sets either through specific depletion by siRNA (KD) or by overexpression (OE).
Mentions: As shown in supplemental Fig. S6, whereas inhibition of PP2A activity led to a linear increase in ERK phosphorylation, that of MEK displayed a bimodal response to PP2A (see also Fig. 8A). The sensitivity of ERK to PP2A activity likely derives from the concomitant decrease in the size of the pool of non-phosphorylated MKP3 as a result of decreasing PP2A levels. As discussed earlier, this would decrease the efficiency of MKP3-dependent dephosphorylation of ERK. In addition to this, however, a diminished pool of phospho-MKP3 would also imply a consequent reduction in the negative regulation of MKP1 and, thereby, an increase in the MKP1-dependent inactivation of ERK.

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