INT196779

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Context Info
Confidence 0.72
First Reported 2005
Last Reported 2010
Negated 2
Speculated 0
Reported most in Body
Documents 28
Total Number 28
Disease Relevance 1.86
Pain Relevance 3.25

This is a graph with borders and nodes. Maybe there is an Imagemap used so the nodes may be linking to some Pages.

cytosol (Ppp2ca) chromosome (Ppp2ca) plasma membrane (Ppp2ca)
cytoskeleton (Ppp2ca) nucleus (Ppp2ca) cytoplasm (Ppp2ca)
Anatomy Link Frequency
PP2A 2
substantia nigra 1
striatum 1
Ppp2ca (Mus musculus)
Pain Link Frequency Relevance Heat
Glutamate 363 99.88 Very High Very High Very High
Dopamine 1602 99.36 Very High Very High Very High
Substantia nigra 138 99.00 Very High Very High Very High
Kinase C 26 93.48 High High
Opioid 16 92.36 High High
adenocard 26 91.52 High High
Catecholamine 84 89.92 High High
Neurotransmitter 59 89.92 High High
depression 37 87.44 High High
antagonist 24 86.64 High High
Disease Link Frequency Relevance Heat
Death 13 100.00 Very High Very High Very High
Targeted Disruption 152 99.34 Very High Very High Very High
Parkinson's Disease 259 98.04 Very High Very High Very High
Apoptosis 50 94.12 High High
Drug Induced Neurotoxicity 2 89.00 High High
Stress 45 87.60 High High
Depression 43 87.44 High High
Disease 59 85.36 High High
Aging 42 79.32 Quite High
Toxicity 42 64.48 Quite High

Sentences Mentioned In

Key: Protein Mutation Event Anatomy Negation Speculation Pain term Disease term
To directly measure the impact of Ser-129 phosphorylation of a-Syn on PP2A and TH, we used recombinant proteins and cell-free assays.


Phosphorylation (phosphorylation) of PP2A
1) Confidence 0.72 Published 2010 Journal The Journal of Biological Chemistry Section Body Doc Link PMC2878529 Disease Relevance 0 Pain Relevance 0.07
PP2A does not dephosphorylate a-Syn Ser-129 (72), and we confirmed this in our experiments where background signal-only was noted for both PLK2+- and PLK2-a-Syn-treated samples (Fig. 7B, left).
Neg (not) Phosphorylation (dephosphorylate) of PP2A
2) Confidence 0.72 Published 2010 Journal The Journal of Biological Chemistry Section Body Doc Link PMC2878529 Disease Relevance 0 Pain Relevance 0
In summary, our work using in vitro models has demonstrated that PP2A dephosphorylates TH-Ser(P)-19 (Fig. 2), that a-Syn activates PP2A and inhibits TH, and further, that a-Syn Ser(P)-129 attenuates both effects (Figs. 5 and 7).
Phosphorylation (dephosphorylates) of PP2A
3) Confidence 0.72 Published 2010 Journal The Journal of Biological Chemistry Section Body Doc Link PMC2878529 Disease Relevance 0.08 Pain Relevance 0.05
To assess the impact of a-Syn loss in vivo, we used striatum from 12-month-old ASKO mice and age-matched Non-Tg controls in which we measured TH phosphorylation, TH activity, and PP2A activity.
Phosphorylation (phosphorylation) of PP2A in striatum
4) Confidence 0.72 Published 2010 Journal The Journal of Biological Chemistry Section Body Doc Link PMC2878529 Disease Relevance 0 Pain Relevance 0.05
To assess if PP2A dephosphorylates TH-Ser(P)-19 in our cells, we first treated untransfected MN9D cells with okadaic acid and measured Ser(P)-19 levels by immunoblot.
Phosphorylation (dephosphorylates) of PP2A
5) Confidence 0.72 Published 2010 Journal The Journal of Biological Chemistry Section Body Doc Link PMC2878529 Disease Relevance 0 Pain Relevance 0
To assess the potential contribution of a-Syn phosphorylation on TH and PP2A activity in a physiological model, we next evaluated MN9D cells after transient transfection with wild type or Ser-129 mutant a-Syn.


Phosphorylation (phosphorylation) of PP2A
6) Confidence 0.72 Published 2010 Journal The Journal of Biological Chemistry Section Body Doc Link PMC2878529 Disease Relevance 0.07 Pain Relevance 0.03
Importantly, Ser(P)-129 is not dephosphorylated by PP2A (72), a finding that we have also reconfirmed (Fig. 7B).
Neg (not) Phosphorylation (dephosphorylated) of PP2A
7) Confidence 0.72 Published 2010 Journal The Journal of Biological Chemistry Section Body Doc Link PMC2878529 Disease Relevance 0.34 Pain Relevance 0
The effect of phosphorylated and unphosphorylated a-Syn on recombinant human PP2A (Cayman Chemical, Ann Arbor, MI) was then measured as detailed below.


Phosphorylation (unphosphorylated) of PP2A
8) Confidence 0.72 Published 2010 Journal The Journal of Biological Chemistry Section Body Doc Link PMC2878529 Disease Relevance 0 Pain Relevance 0.03
Data from repeated okadaic acid experiments confirmed significantly higher TH-Ser(P)-19 levels in WT-Syn cells compared with control MN9D cells (Fig. 2D; p < 0.001, Student's t test), findings that firmly support the role of PP2A in TH-Ser-19 dephosphorylation in MN9D cells.
Phosphorylation (dephosphorylation) of PP2A
9) Confidence 0.72 Published 2010 Journal The Journal of Biological Chemistry Section Body Doc Link PMC2878529 Disease Relevance 0 Pain Relevance 0
Conversely, a-Syn knock-out mice had elevated TH-Ser-19 phosphorylation and activity and less active PP2A in dopaminergic tissues.
Phosphorylation (phosphorylation) of PP2A in PP2A associated with targeted disruption
10) Confidence 0.62 Published 2010 Journal The Journal of Biological Chemistry Section Abstract Doc Link PMC2878529 Disease Relevance 0.16 Pain Relevance 0.11
, anti-Glut4, anti-AMPK, anti-phosphorylated AMPK (pAMPK, Thr172), anti-ACC, anti-phosphorylated ACC (pACC, Ser79), anti-LKB1, anti-phosphorylated LKB1 (pLKB1, Ser428), anti-PP2AA, anti-PP2AB, anti-PP2C?
Phosphorylation (phosphorylated) of PP2AA
11) Confidence 0.57 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2890411 Disease Relevance 0 Pain Relevance 0
Importantly, Ser(P)-129 is not dephosphorylated by PP2A (72), a finding that we verified (Fig. 7B). a-Syn can be phosphorylated by at least three kinases, including casein kinase 2 (72, 96–99), G-protein-coupled receptor kinase 5 (100), and Polo-like kinases, especially PLK2, which exclusively phosphorylates Ser-129 (101).
Phosphorylation (phosphorylated) of PP2A
12) Confidence 0.56 Published 2010 Journal The Journal of Biological Chemistry Section Body Doc Link PMC2878529 Disease Relevance 0.49 Pain Relevance 0.16
ERK phosphorylation was diminished in a-Syn cells compared with GFP-transfected MN9D controls, and furthermore, inhibition of PP2A increased ERK phosphorylation in our cells (data not shown), suggesting that only a-Syn interacting proteins were affected by a-Syn-mediated PP2A activation.
Phosphorylation (phosphorylation) of PP2A
13) Confidence 0.56 Published 2010 Journal The Journal of Biological Chemistry Section Body Doc Link PMC2878529 Disease Relevance 0 Pain Relevance 0.03
Here we assessed the impact of a-Syn phosphorylation on TH and PP2A in vivo, by transducing substantia nigra of ASKO mice with GFP, WT-Syn, or S129A-Syn lentivirus.
Phosphorylation (phosphorylation) of PP2A in substantia nigra associated with substantia nigra
14) Confidence 0.56 Published 2010 Journal The Journal of Biological Chemistry Section Body Doc Link PMC2878529 Disease Relevance 0 Pain Relevance 0.08
Therefore, the third aim of this study was to assess if phosphorylation of a-Syn, in particular of Ser-129, affected PP2A or TH activity in vitro or in vivo.
Phosphorylation (phosphorylation) of PP2A
15) Confidence 0.56 Published 2010 Journal The Journal of Biological Chemistry Section Body Doc Link PMC2878529 Disease Relevance 0.09 Pain Relevance 0
PKAc enhancement of PP2A activity (reaction (i) in Figure 6E); PP2A dephosphorylation of phosphoThr75 (reaction (ii)); and subsequent decreased inhibition of PKAc (reaction (iii)) can act on PKAc as a positive feedback loop.
Phosphorylation (dephosphorylation) of PP2A
16) Confidence 0.52 Published 2006 Journal PLoS Computational Biology Section Body Doc Link PMC1562452 Disease Relevance 0 Pain Relevance 0.34
Eliminating just the phosphorylation of PP2A by PKAc (reaction (i), magenta lines), or eliminating just the inhibition of PKA by phosphoThr75 (reaction (iii), light blue lines), produces a small increase in PKAc, but eliminating both reactions produces a dramatically larger increase in PKAc.
Phosphorylation (phosphorylation) of PP2A
17) Confidence 0.52 Published 2006 Journal PLoS Computational Biology Section Body Doc Link PMC1562452 Disease Relevance 0 Pain Relevance 0.17
Lacking experimental measurements of specific activity of calcium-activated PP2A, the activity of PP2Ac is set the same as that for phosphorylated PP2A.
Phosphorylation (phosphorylated) of PP2A
18) Confidence 0.52 Published 2006 Journal PLoS Computational Biology Section Body Doc Link PMC1562452 Disease Relevance 0 Pain Relevance 0.07
Removing the phosphorylation of PP2A by PKAc should decrease the modulation of phosphoThr75, and reduce the disinhibition of PKAc.
Phosphorylation (phosphorylation) of PP2A
19) Confidence 0.52 Published 2006 Journal PLoS Computational Biology Section Body Doc Link PMC1562452 Disease Relevance 0 Pain Relevance 0.21
Additional model simulations show that enhanced activation of PP2A via phosphorylation by PKA is required to produce the decrease in phosphoThr75.
Phosphorylation (phosphorylation) of PP2A
20) Confidence 0.52 Published 2006 Journal PLoS Computational Biology Section Body Doc Link PMC1562452 Disease Relevance 0 Pain Relevance 0.29

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