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complex(GO:"protein phosphatase type 2A complex")

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Entity

Name
protein phosphatase type 2A complex
Namespace
go
Namespace Version
20180921
Namespace URL
https://raw.githubusercontent.com/pharmacome/terminology/b46b65c3da259b6e86026514dfececab7c22a11b/external/go-names.belns

Appears in Networks 3

Tau Modifications v1.9.5

Tau Modifications Sections of NESTOR

Assembly and structure of protein phosphatase 2A v1.0.0

Protein phosphatase 2A dysfunction in Alzheimer’s disease v1.0.0

In-Edges 71

p(HBP:"APOE e4") negativeCorrelation complex(GO:"protein phosphatase type 2A complex") View Subject | View Object

Our results indicated a significant down-regulation of PPP2R5E gene expression and reduction in PP2A activity by ApoE4 compared with ApoE3. This may also explain an elevated Tau phosphorylation in AD human brains that featured at least one ApoE4 allele. PubMed:28720530

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p(HGNC:PPP2R5E) partOf complex(GO:"protein phosphatase type 2A complex") View Subject | View Object

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a(CHEBI:"microcystin-LR") decreases act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

Two potent tumor-inducing toxins, okadaic acid (OA) and microcystin-LR (MCLR), specifically inhibit PP2A PubMed:19277525

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a(CHEBI:"okadaic acid") decreases act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

Two potent tumor-inducing toxins, okadaic acid (OA) and microcystin-LR (MCLR), specifically inhibit PP2A PubMed:19277525

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p(HGNC:PPME1) decreases act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

Structural observations clearly indicate that PME-1 inactivates the phosphatase activity of PP2A PubMed:19277525

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p(HGNC:PPP2CA) increases complex(GO:"protein phosphatase type 2A complex") View Subject | View Object

Previous studies suggested that carboxy-methylation of the catalytic subunit played an important role in the assembly of heterotrimeric PP2A holoenzymes in cells PubMed:19277525

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complex(p(HGNC:PPP2CA, pmod(Me)), p(HGNC:PPP2R1A)) increases complex(GO:"protein phosphatase type 2A complex") View Subject | View Object

In addition, the methylated carboxy-terminus might help recruit assembly factors that actively promote assembly of the PP2A holoenzymes in cells. PubMed:19277525

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composite(p(HGNC:PPME1), p(HGNC:PPP2CA), p(HGNC:PPP2R1A)) negativeCorrelation act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

The PP2A core enzyme, upon initial incubation with various concentrations of PME-1, exhibited full Ser/Thr phosphatase activity and, only after prolonged incubation time, had substantial loss of the phosphatase activity PubMed:19277525

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p(HGNC:LCMT1) causesNoChange act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

A portion of cellular PP2A stably associated with PME-1 and was catalytically inactive [80]; intriguingly, this inactive portion of PP2A could be re-activated by PP2A phosphatase activator (PTPA), but not by LCMT1, ruling out the possibility that inactivation was solely caused by demethylation PubMed:19277525

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p(HGNC:PTPA) increases act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

A portion of cellular PP2A stably associated with PME-1 and was catalytically inactive [80]; intriguingly, this inactive portion of PP2A could be re-activated by PP2A phosphatase activator (PTPA), but not by LCMT1, ruling out the possibility that inactivation was solely caused by demethylation PubMed:19277525

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a(CHEBI:"metal cation") increases act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

Conversely, many endogenous small molecules, comprising metal cations, ceramides and polyamines, can enhance the activity of PP2A enzymes (Reviewed in Voronkov et al.,2011). PubMed:24653673

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a(CHEBI:"okadaic acid") decreases act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

Natural toxins such as okadaic acid, calyculin ,and fostriecin (Reviewed in Swingle et al., 2007), and endogenous nuclear inhibitors called I1 PP2A and I2 PP2A/SET (Li and Damuni, 1998), can directly bind to the catalytic subunit and inhibit the phosphatase activity of the entire family of PP2A enzymes. PubMed:24653673

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a(CHEBI:"okadaic acid") decreases act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

In vivo use of phosphatase inhibitors such as okadaic acid has been shown in many studies to induce cognitive impairment and widespread neurotoxic effects that are reminiscent of the hallmark pathological processes occurring in AD pathology, i.e., the accumulation of P-tau, amyloidogenesis, synapse loss and neurodegeneration (Malchiodi-Albedi et al., 1997; Arendt et al., 1998; Sun et al.,2003; Kamat et al.,2013) PubMed:24653673

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a(CHEBI:ceramide) increases act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

Conversely, many endogenous small molecules, comprising metal cations, ceramides and polyamines, can enhance the activity of PP2A enzymes (Reviewed in Voronkov et al.,2011). PubMed:24653673

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a(CHEBI:polyamine) increases act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

Conversely, many endogenous small molecules, comprising metal cations, ceramides and polyamines, can enhance the activity of PP2A enzymes (Reviewed in Voronkov et al.,2011). PubMed:24653673

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a(PUBCHEM:5311365) decreases act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

Natural toxins such as okadaic acid, calyculin ,and fostriecin (Reviewed in Swingle et al., 2007), and endogenous nuclear inhibitors called I1 PP2A and I2 PP2A/SET (Li and Damuni, 1998), can directly bind to the catalytic subunit and inhibit the phosphatase activity of the entire family of PP2A enzymes. PubMed:24653673

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a(PUBCHEM:6913994) decreases act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

Natural toxins such as okadaic acid, calyculin ,and fostriecin (Reviewed in Swingle et al., 2007), and endogenous nuclear inhibitors called I1 PP2A and I2 PP2A/SET (Li and Damuni, 1998), can directly bind to the catalytic subunit and inhibit the phosphatase activity of the entire family of PP2A enzymes. PubMed:24653673

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complex(a(CHEBI:"okadaic acid"), p(HGNC:PPP2CA)) decreases act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

Natural toxins such as okadaic acid, calyculin ,and fostriecin (Reviewed in Swingle et al., 2007), and endogenous nuclear inhibitors called I1 PP2A and I2 PP2A/SET (Li and Damuni, 1998), can directly bind to the catalytic subunit and inhibit the phosphatase activity of the entire family of PP2A enzymes. PubMed:24653673

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p(HGNC:PPP2CA) association act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

Deficits in PP2A activity are in line with the reported down-regulation of PP2A catalytic C subunit at the gene (Loring et al.,2001), mRNA (Vogelsberg-Ragaglia et al.,2001) and protein (Sontag et al.,2004b) expression levels in AD. PubMed:24653673

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complex(a(CHEBI:"okadaic acid"), p(HGNC:PPP2CB)) decreases act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

Natural toxins such as okadaic acid, calyculin ,and fostriecin (Reviewed in Swingle et al., 2007), and endogenous nuclear inhibitors called I1 PP2A and I2 PP2A/SET (Li and Damuni, 1998), can directly bind to the catalytic subunit and inhibit the phosphatase activity of the entire family of PP2A enzymes. PubMed:24653673

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p(HGNC:PPP2CB) association act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

Deficits in PP2A activity are in line with the reported down-regulation of PP2A catalytic C subunit at the gene (Loring et al.,2001), mRNA (Vogelsberg-Ragaglia et al.,2001) and protein (Sontag et al.,2004b) expression levels in AD. PubMed:24653673

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act(p(HGNC:GSK3B)) decreases act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

For instance, activated GSK3β has been reported to induce PP2A inactivation via several mechanisms: phosphorylation of PP2A on Tyr307 (Yao et al.,2011); demethylation of PP2A on Leu309 through inhibition of LCMT1 and up-regulation of PME1 (Yao et al.,2012); and accumulation of I2 PP2A (Liu et al.,2008a). PubMed:24653673

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complex(a(PUBCHEM:5311365), p(HGNC:PPP2CA)) decreases act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

Natural toxins such as okadaic acid, calyculin ,and fostriecin (Reviewed in Swingle et al., 2007), and endogenous nuclear inhibitors called I1 PP2A and I2 PP2A/SET (Li and Damuni, 1998), can directly bind to the catalytic subunit and inhibit the phosphatase activity of the entire family of PP2A enzymes. PubMed:24653673

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complex(a(PUBCHEM:5311365), p(HGNC:PPP2CB)) decreases act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

Natural toxins such as okadaic acid, calyculin ,and fostriecin (Reviewed in Swingle et al., 2007), and endogenous nuclear inhibitors called I1 PP2A and I2 PP2A/SET (Li and Damuni, 1998), can directly bind to the catalytic subunit and inhibit the phosphatase activity of the entire family of PP2A enzymes. PubMed:24653673

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complex(a(PUBCHEM:6913994), p(HGNC:PPP2CA)) decreases act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

Natural toxins such as okadaic acid, calyculin ,and fostriecin (Reviewed in Swingle et al., 2007), and endogenous nuclear inhibitors called I1 PP2A and I2 PP2A/SET (Li and Damuni, 1998), can directly bind to the catalytic subunit and inhibit the phosphatase activity of the entire family of PP2A enzymes. PubMed:24653673

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complex(a(PUBCHEM:6913994), p(HGNC:PPP2CB)) decreases act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

Natural toxins such as okadaic acid, calyculin ,and fostriecin (Reviewed in Swingle et al., 2007), and endogenous nuclear inhibitors called I1 PP2A and I2 PP2A/SET (Li and Damuni, 1998), can directly bind to the catalytic subunit and inhibit the phosphatase activity of the entire family of PP2A enzymes. PubMed:24653673

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complex(p(HGNC:ANP32A), p(HGNC:PPP2CA)) decreases act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

Natural toxins such as okadaic acid, calyculin ,and fostriecin (Reviewed in Swingle et al., 2007), and endogenous nuclear inhibitors called I1 PP2A and I2 PP2A/SET (Li and Damuni, 1998), can directly bind to the catalytic subunit and inhibit the phosphatase activity of the entire family of PP2A enzymes. PubMed:24653673

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p(HGNC:ANP32A) decreases act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

Natural toxins such as okadaic acid, calyculin ,and fostriecin (Reviewed in Swingle et al., 2007), and endogenous nuclear inhibitors called I1 PP2A and I2 PP2A/SET (Li and Damuni, 1998), can directly bind to the catalytic subunit and inhibit the phosphatase activity of the entire family of PP2A enzymes. PubMed:24653673

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p(HGNC:ANP32A) negativeCorrelation act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

Up-regulation of I1 PP2A and I2 PP2A, and mislocalization and cleavage of I2 PP2A, could underlie the inactivation of PP2A in AD neocortical neurons (Tanimukai et al.,2005). PubMed:24653673

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Annotations
MeSH
Neocortex
MeSH
Alzheimer Disease

complex(p(HGNC:ANP32A), p(HGNC:PPP2CB)) decreases act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

Natural toxins such as okadaic acid, calyculin ,and fostriecin (Reviewed in Swingle et al., 2007), and endogenous nuclear inhibitors called I1 PP2A and I2 PP2A/SET (Li and Damuni, 1998), can directly bind to the catalytic subunit and inhibit the phosphatase activity of the entire family of PP2A enzymes. PubMed:24653673

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complex(p(HGNC:IGBP1), p(HGNC:PPP2CA)) regulates complex(GO:"protein phosphatase type 2A complex") View Subject | View Object

Furthermore, direct interaction of PP2A catalytic subunit with specific regulatory proteins, including PME-1, LCMT1, the alpha4 subunit, and the PP2A phosphatase activator PTPA, critically modulates PP2A biogenesis and stability PubMed:24653673

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complex(p(HGNC:IGBP1), p(HGNC:PPP2CB)) regulates complex(GO:"protein phosphatase type 2A complex") View Subject | View Object

Furthermore, direct interaction of PP2A catalytic subunit with specific regulatory proteins, including PME-1, LCMT1, the alpha4 subunit, and the PP2A phosphatase activator PTPA, critically modulates PP2A biogenesis and stability PubMed:24653673

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complex(p(HGNC:LCMT1), p(HGNC:PPP2CA)) regulates complex(GO:"protein phosphatase type 2A complex") View Subject | View Object

Furthermore, direct interaction of PP2A catalytic subunit with specific regulatory proteins, including PME-1, LCMT1, the alpha4 subunit, and the PP2A phosphatase activator PTPA, critically modulates PP2A biogenesis and stability PubMed:24653673

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complex(p(HGNC:LCMT1), p(HGNC:PPP2CB)) regulates complex(GO:"protein phosphatase type 2A complex") View Subject | View Object

Furthermore, direct interaction of PP2A catalytic subunit with specific regulatory proteins, including PME-1, LCMT1, the alpha4 subunit, and the PP2A phosphatase activator PTPA, critically modulates PP2A biogenesis and stability PubMed:24653673

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p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55") increases act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

For instance, the Bα subunit specifically and markedly facilitates dephosphory- lation of tau by PP2A (Sontag et al.,1996; Xu et al.,2008). PubMed:24653673

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complex(p(HGNC:PPME1), p(HGNC:PPP2CA)) decreases act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

Conversely, the PP2A-specific methylesterase PME-1 can directly bind to the active site of the catalytic subunit, remove the methyl group and inactivate PP2A by evicting manganese ions required for phosphatase activity (Xing et al.,2008). PubMed:24653673

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complex(p(HGNC:PPME1), p(HGNC:PPP2CA)) regulates complex(GO:"protein phosphatase type 2A complex") View Subject | View Object

Furthermore, direct interaction of PP2A catalytic subunit with specific regulatory proteins, including PME-1, LCMT1, the alpha4 subunit, and the PP2A phosphatase activator PTPA, critically modulates PP2A biogenesis and stability PubMed:24653673

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p(HGNC:PPME1) negativeCorrelation act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

For example, PME-1 stabilizes a nuclear pool of inactive PP2A enzymes (Longin et al., 2008), while methylation by LCMT1 influences the amounts of PP2A enzymes bound to plasma membrane microdomains (Sontag et al.,2013). PubMed:24653673

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Annotations
MeSH
Cell Nucleus

complex(p(HGNC:PPME1), p(HGNC:PPP2CB)) decreases act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

Conversely, the PP2A-specific methylesterase PME-1 can directly bind to the active site of the catalytic subunit, remove the methyl group and inactivate PP2A by evicting manganese ions required for phosphatase activity (Xing et al.,2008). PubMed:24653673

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complex(p(HGNC:PPME1), p(HGNC:PPP2CB)) regulates complex(GO:"protein phosphatase type 2A complex") View Subject | View Object

Furthermore, direct interaction of PP2A catalytic subunit with specific regulatory proteins, including PME-1, LCMT1, the alpha4 subunit, and the PP2A phosphatase activator PTPA, critically modulates PP2A biogenesis and stability PubMed:24653673

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complex(p(HGNC:PPP2CA), p(HGNC:PTPA)) regulates complex(GO:"protein phosphatase type 2A complex") View Subject | View Object

Furthermore, direct interaction of PP2A catalytic subunit with specific regulatory proteins, including PME-1, LCMT1, the alpha4 subunit, and the PP2A phosphatase activator PTPA, critically modulates PP2A biogenesis and stability PubMed:24653673

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p(HGNC:PTPA) increases act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

Decreased expression levels of PTPA in AD brain tissue may also lead to inactivation of PP2A by indirectly increasing levels of PP2A phosphorylated at the Tyr-307 site (Luo et al.,2013). PubMed:24653673

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Annotations
MeSH
Alzheimer Disease

complex(p(HGNC:PPP2CA), p(HGNC:SET)) decreases act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

Natural toxins such as okadaic acid, calyculin ,and fostriecin (Reviewed in Swingle et al., 2007), and endogenous nuclear inhibitors called I1 PP2A and I2 PP2A/SET (Li and Damuni, 1998), can directly bind to the catalytic subunit and inhibit the phosphatase activity of the entire family of PP2A enzymes. PubMed:24653673

Appears in Networks:

p(HGNC:SET) decreases act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

Natural toxins such as okadaic acid, calyculin ,and fostriecin (Reviewed in Swingle et al., 2007), and endogenous nuclear inhibitors called I1 PP2A and I2 PP2A/SET (Li and Damuni, 1998), can directly bind to the catalytic subunit and inhibit the phosphatase activity of the entire family of PP2A enzymes. PubMed:24653673

Appears in Networks:

p(HGNC:SET) negativeCorrelation act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

Up-regulation of I1 PP2A and I2 PP2A, and mislocalization and cleavage of I2 PP2A, could underlie the inactivation of PP2A in AD neocortical neurons (Tanimukai et al.,2005). PubMed:24653673

Appears in Networks:
Annotations
MeSH
Neocortex
MeSH
Alzheimer Disease

p(HGNC:SET) negativeCorrelation act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

For instance, activated GSK3β has been reported to induce PP2A inactivation via several mechanisms: phosphorylation of PP2A on Tyr307 (Yao et al.,2011); demethylation of PP2A on Leu309 through inhibition of LCMT1 and up-regulation of PME1 (Yao et al.,2012); and accumulation of I2 PP2A (Liu et al.,2008a). PubMed:24653673

Appears in Networks:

complex(p(HGNC:PPP2CB), p(HGNC:PTPA)) regulates complex(GO:"protein phosphatase type 2A complex") View Subject | View Object

Furthermore, direct interaction of PP2A catalytic subunit with specific regulatory proteins, including PME-1, LCMT1, the alpha4 subunit, and the PP2A phosphatase activator PTPA, critically modulates PP2A biogenesis and stability PubMed:24653673

Appears in Networks:

complex(p(HGNC:PPP2CB), p(HGNC:SET)) decreases act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

Natural toxins such as okadaic acid, calyculin ,and fostriecin (Reviewed in Swingle et al., 2007), and endogenous nuclear inhibitors called I1 PP2A and I2 PP2A/SET (Li and Damuni, 1998), can directly bind to the catalytic subunit and inhibit the phosphatase activity of the entire family of PP2A enzymes. PubMed:24653673

Appears in Networks:

p(FPLX:PPP2, pmod(Ph, Tyr, 307)) negativeCorrelation act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

Decreased expression levels of PTPA in AD brain tissue may also lead to inactivation of PP2A by indirectly increasing levels of PP2A phosphorylated at the Tyr-307 site (Luo et al.,2013). PubMed:24653673

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(FPLX:PPP2, pmod(Ph, Tyr, 307)) decreases act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

For instance, activated GSK3β has been reported to induce PP2A inactivation via several mechanisms: phosphorylation of PP2A on Tyr307 (Yao et al.,2011); demethylation of PP2A on Leu309 through inhibition of LCMT1 and up-regulation of PME1 (Yao et al.,2012); and accumulation of I2 PP2A (Liu et al.,2008a). PubMed:24653673

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p(HGNC:IGBP1, frag("?")) regulates complex(GO:"protein phosphatase type 2A complex") View Subject | View Object

Lastly, increased calpain-mediated cleavage of alpha4, which critically modulates PP2A stability, could be responsible for increased degradation of PP2A catalytic subunit in AD (Watkins et al., 2012). PubMed:24653673

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p(HGNC:PPP2CA, pmod(HBP:nitration, Tyr)) increases act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

Other modifications of PP2AC subunit include ubiquitination, which targets PP2A for degradation (McConnelletal.,2010), and tyrosine nitration that increases PP2A activity in endothelial cells (Wu and Wilson, 2009). PubMed:24653673

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Annotations
MeSH
Endothelial Cells

p(HGNC:PPP2CA, pmod(Me, Leu, 309)) increases complex(GO:"protein phosphatase type 2A complex") View Subject | View Object

Methylation is thought to play a critical role in the biogenesis of PP2A holoenzymes. PubMed:24653673

Appears in Networks:

p(HGNC:PPP2CA, pmod(Me, Leu, 309)) increases act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

For instance, activated GSK3β has been reported to induce PP2A inactivation via several mechanisms: phosphorylation of PP2A on Tyr307 (Yao et al.,2011); demethylation of PP2A on Leu309 through inhibition of LCMT1 and up-regulation of PME1 (Yao et al.,2012); and accumulation of I2 PP2A (Liu et al.,2008a). PubMed:24653673

Appears in Networks:

p(HGNC:PPP2CA, pmod(Ph, Tyr, 307)) increases act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

PP2A enzymes can also become transiently inactivated following tyrosine phosphorylation of the catalytic subunit at the putative Tyr-307 site,via activation of src kinase, epidermal growth factor receptor or insulin signaling (Chen et al.,1992). PubMed:24653673

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p(HGNC:PPP2CA, pmod(Ph, Tyr, 307)) decreases act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

Besides Ser/Thr kinases, the protein tyrosine kinase src promotes the phosphorylation of PP2A on Tyr-307, resulting in PP2A inactivation and subsequent tau phosphorylation (Xiong et al.,2013; Arif et al.,2014). PubMed:24653673

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p(HGNC:PPP2CA, pmod(Ub)) increases deg(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

Other modifications of PP2AC subunit include ubiquitination, which targets PP2A for degradation (McConnelletal.,2010), and tyrosine nitration that increases PP2A activity in endothelial cells (Wu and Wilson, 2009). PubMed:24653673

Appears in Networks:

p(HGNC:PPP2CB, pmod(Me, Leu, 309)) increases complex(GO:"protein phosphatase type 2A complex") View Subject | View Object

Methylation is thought to play a critical role in the biogenesis of PP2A holoenzymes. PubMed:24653673

Appears in Networks:

p(HGNC:PPP2CB, pmod(Me, Leu, 309)) increases act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

For instance, activated GSK3β has been reported to induce PP2A inactivation via several mechanisms: phosphorylation of PP2A on Tyr307 (Yao et al.,2011); demethylation of PP2A on Leu309 through inhibition of LCMT1 and up-regulation of PME1 (Yao et al.,2012); and accumulation of I2 PP2A (Liu et al.,2008a). PubMed:24653673

Appears in Networks:

p(HGNC:PPP2CB, pmod(Ph, Tyr, 307)) increases act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

PP2A enzymes can also become transiently inactivated following tyrosine phosphorylation of the catalytic subunit at the putative Tyr-307 site,via activation of src kinase, epidermal growth factor receptor or insulin signaling (Chen et al.,1992). PubMed:24653673

Appears in Networks:

p(HGNC:PPP2CB, pmod(Ph, Tyr, 307)) decreases act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

Besides Ser/Thr kinases, the protein tyrosine kinase src promotes the phosphorylation of PP2A on Tyr-307, resulting in PP2A inactivation and subsequent tau phosphorylation (Xiong et al.,2013; Arif et al.,2014). PubMed:24653673

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p(HGNC:PPP2R1A, pmod(Ph, Ser), pmod(Ph, Thr)) decreases act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

A recent report also indicates the existence of regulated phosphorylation of the scaffolding A subunit on Ser/Thr residues, which affects its binding to the catalytic subunit and PP2A signaling in the heart (Kotlo et al.,2014). PubMed:24653673

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Annotations
MeSH
Heart

p(HGNC:PPP2R1B, pmod(Ph, Ser), pmod(Ph, Thr)) decreases act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

A recent report also indicates the existence of regulated phosphorylation of the scaffolding A subunit on Ser/Thr residues, which affects its binding to the catalytic subunit and PP2A signaling in the heart (Kotlo et al.,2014). PubMed:24653673

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Annotations
MeSH
Heart

p(HGNC:PPP2R5A, pmod(Ph, Ser)) regulates act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

Adding another layer of complexity to the regulation of PP2A holoenzymes, protein kinase A-mediated serine phosphorylation of selective PPP2R5A and PPP2R5D regulatory subunits belonging to the B’family can also modulate PP2A catalytic activity (Ahn et al.,2007; Kirchhefer et al.,2014). PubMed:24653673

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p(HGNC:PPP2R5D, pmod(Ph, Ser)) regulates act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

Adding another layer of complexity to the regulation of PP2A holoenzymes, protein kinase A-mediated serine phosphorylation of selective PPP2R5A and PPP2R5D regulatory subunits belonging to the B’family can also modulate PP2A catalytic activity (Ahn et al.,2007; Kirchhefer et al.,2014). PubMed:24653673

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p(HGNC:SET, frag("?")) negativeCorrelation act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

Up-regulation of I1 PP2A and I2 PP2A, and mislocalization and cleavage of I2 PP2A, could underlie the inactivation of PP2A in AD neocortical neurons (Tanimukai et al.,2005). PubMed:24653673

Appears in Networks:
Annotations
MeSH
Neocortex
MeSH
Alzheimer Disease

p(INTERPRO:"Protein phosphatase 2A, regulatory B subunit, B56") increases tloc(complex(GO:"protein phosphatase type 2A complex"), fromLoc(GO:cytoplasm), toLoc(GO:nucleus)) View Subject | View Object

For instance, some B’ subunits target PP2A to the nucleus (McCright et al., 1996) or the centrosome (Flegg et al.,2010); Bα subunits can direct some PP2A pools to microtubules, which could serve as a cytoskeletal reservoir of inac- tive enzymes (Sontag et al.,1995; Hiraga and Tamura,2000). PubMed:24653673

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p(INTERPRO:"Protein phosphatase 2A, regulatory B subunit, B56") increases tloc(complex(GO:"protein phosphatase type 2A complex"), fromLoc(GO:cytoplasm), toLoc(GO:centrosome)) View Subject | View Object

For instance, some B’ subunits target PP2A to the nucleus (McCright et al., 1996) or the centrosome (Flegg et al.,2010); Bα subunits can direct some PP2A pools to microtubules, which could serve as a cytoskeletal reservoir of inac- tive enzymes (Sontag et al.,1995; Hiraga and Tamura,2000). PubMed:24653673

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path(MESH:"Alzheimer Disease") negativeCorrelation act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

There is a significant decrease in total PP2A activity measured in AD cortical and hippocampal brain homogenates (Gong et al.,1993; Gong et al.,1995; Sontag et al.,2004b). PubMed:24653673

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Annotations
MeSH
Cerebral Cortex
MeSH
Hippocampus

path(MESH:"Alzheimer Disease") positiveCorrelation complex(GO:"protein phosphatase type 2A complex") View Subject | View Object

In contrast, “PP2A” expression levels are increased in AD astrocytes (Pei et al., 1997). PubMed:24653673

Appears in Networks:
Annotations
MeSH
Astrocytes

path(MESH:"Alzheimer Disease") negativeCorrelation act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

Collectively, those studies point to a central role for PP2A dysfunction in AD pathogenesis PubMed:24653673

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Out-Edges 35

complex(GO:"protein phosphatase type 2A complex") negativeCorrelation p(HBP:"APOE e4") View Subject | View Object

Our results indicated a significant down-regulation of PPP2R5E gene expression and reduction in PP2A activity by ApoE4 compared with ApoE3. This may also explain an elevated Tau phosphorylation in AD human brains that featured at least one ApoE4 allele. PubMed:28720530

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complex(GO:"protein phosphatase type 2A complex") regulates bp(GO:"cell cycle") View Subject | View Object

PP2A plays a critical role in cellular physiology including cell cycle regulation, cell proliferation and death, development, cytoskeleton dynamics, cell mobility, and regulation of multiple signal transduction pathways PubMed:19277525

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complex(GO:"protein phosphatase type 2A complex") regulates bp(GO:"cell population proliferation") View Subject | View Object

PP2A plays a critical role in cellular physiology including cell cycle regulation, cell proliferation and death, development, cytoskeleton dynamics, cell mobility, and regulation of multiple signal transduction pathways PubMed:19277525

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complex(GO:"protein phosphatase type 2A complex") regulates bp(GO:"cell death") View Subject | View Object

PP2A plays a critical role in cellular physiology including cell cycle regulation, cell proliferation and death, development, cytoskeleton dynamics, cell mobility, and regulation of multiple signal transduction pathways PubMed:19277525

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complex(GO:"protein phosphatase type 2A complex") regulates act(a(GO:cytoskeleton)) View Subject | View Object

PP2A plays a critical role in cellular physiology including cell cycle regulation, cell proliferation and death, development, cytoskeleton dynamics, cell mobility, and regulation of multiple signal transduction pathways PubMed:19277525

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complex(GO:"protein phosphatase type 2A complex") regulates bp(GO:"cell motility") View Subject | View Object

PP2A plays a critical role in cellular physiology including cell cycle regulation, cell proliferation and death, development, cytoskeleton dynamics, cell mobility, and regulation of multiple signal transduction pathways PubMed:19277525

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complex(GO:"protein phosphatase type 2A complex") regulates bp(GO:"signal transduction") View Subject | View Object

PP2A plays a critical role in cellular physiology including cell cycle regulation, cell proliferation and death, development, cytoskeleton dynamics, cell mobility, and regulation of multiple signal transduction pathways PubMed:19277525

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complex(GO:"protein phosphatase type 2A complex") hasComponent p(HGNC:PPP2R1A) View Subject | View Object

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complex(GO:"protein phosphatase type 2A complex") hasComponent p(HGNC:PPP2CA) View Subject | View Object

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complex(GO:"protein phosphatase type 2A complex") increases bp(GO:"protein dephosphorylation") View Subject | View Object

PP2A functions by removing phosphate groups from substrate phosphoproteins PubMed:19277525

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complex(GO:"protein phosphatase type 2A complex") decreases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

A key function of PP2A is thought to dephosphorylate the hyperphosphorylated Tau protein PubMed:19277525

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act(complex(GO:"protein phosphatase type 2A complex")) negativeCorrelation composite(p(HGNC:PPME1), p(HGNC:PPP2CA), p(HGNC:PPP2R1A)) View Subject | View Object

The PP2A core enzyme, upon initial incubation with various concentrations of PME-1, exhibited full Ser/Thr phosphatase activity and, only after prolonged incubation time, had substantial loss of the phosphatase activity PubMed:19277525

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act(complex(GO:"protein phosphatase type 2A complex")) association p(HGNC:PPP2CB) View Subject | View Object

Deficits in PP2A activity are in line with the reported down-regulation of PP2A catalytic C subunit at the gene (Loring et al.,2001), mRNA (Vogelsberg-Ragaglia et al.,2001) and protein (Sontag et al.,2004b) expression levels in AD. PubMed:24653673

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complex(GO:"protein phosphatase type 2A complex") increases complex(a(GO:"protein phosphatase type 2A complex"), p(HGNC:GSK3B)) View Subject | View Object

PP2A enzymes can also associate with protein kinases that have been linked to AD, such as glycogen synthase kinase 3β (GSK3β) and cyclin-dependent kinase 5 (cdk5; Plattner et al.,2006), and neuronal receptors, e.g., the NMDA receptor (Chan and Sucher, 2001) and the metabotropic glutamate receptor 5 (Mao et al., 2005; Arif et al., 2014). PubMed:24653673

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complex(GO:"protein phosphatase type 2A complex") decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

For instance, the Bα subunit specifically and markedly facilitates dephosphory- lation of tau by PP2A (Sontag et al.,1996; Xu et al.,2008). PubMed:24653673

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act(complex(GO:"protein phosphatase type 2A complex")) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Besides Ser/Thr kinases, the protein tyrosine kinase src promotes the phosphorylation of PP2A on Tyr-307, resulting in PP2A inactivation and subsequent tau phosphorylation (Xiong et al.,2013; Arif et al.,2014). PubMed:24653673

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act(complex(GO:"protein phosphatase type 2A complex")) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

While many PP2A holoenzymes have the potential to indirectly affect tau phosphorylation by modulating key tau protein kinases (For example see Louis et al., 2011), biochemical and structural studies have demonstrated that PP2A/Bα is the primary PP2A isoform that mediates tau dephosphorylation (Sontag et al.,1996, 1999; Xu et al.,2008). PubMed:24653673

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complex(GO:"protein phosphatase type 2A complex") increases complex(a(GO:"protein phosphatase type 2A complex"), p(HGNC:CDK5)) View Subject | View Object

PP2A enzymes can also associate with protein kinases that have been linked to AD, such as glycogen synthase kinase 3β (GSK3β) and cyclin-dependent kinase 5 (cdk5; Plattner et al.,2006), and neuronal receptors, e.g., the NMDA receptor (Chan and Sucher, 2001) and the metabotropic glutamate receptor 5 (Mao et al., 2005; Arif et al., 2014). PubMed:24653673

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complex(GO:"protein phosphatase type 2A complex") increases complex(a(GO:"protein phosphatase type 2A complex"), a(MESH:"Receptors, N-Methyl-D-Aspartate")) View Subject | View Object

PP2A enzymes can also associate with protein kinases that have been linked to AD, such as glycogen synthase kinase 3β (GSK3β) and cyclin-dependent kinase 5 (cdk5; Plattner et al.,2006), and neuronal receptors, e.g., the NMDA receptor (Chan and Sucher, 2001) and the metabotropic glutamate receptor 5 (Mao et al., 2005; Arif et al., 2014). PubMed:24653673

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complex(GO:"protein phosphatase type 2A complex") increases complex(a(GO:"protein phosphatase type 2A complex"), p(HGNC:GRM5)) View Subject | View Object

PP2A enzymes can also associate with protein kinases that have been linked to AD, such as glycogen synthase kinase 3β (GSK3β) and cyclin-dependent kinase 5 (cdk5; Plattner et al.,2006), and neuronal receptors, e.g., the NMDA receptor (Chan and Sucher, 2001) and the metabotropic glutamate receptor 5 (Mao et al., 2005; Arif et al., 2014). PubMed:24653673

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act(complex(GO:"protein phosphatase type 2A complex")) negativeCorrelation p(HGNC:PPME1) View Subject | View Object

For example, PME-1 stabilizes a nuclear pool of inactive PP2A enzymes (Longin et al., 2008), while methylation by LCMT1 influences the amounts of PP2A enzymes bound to plasma membrane microdomains (Sontag et al.,2013). PubMed:24653673

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Annotations
MeSH
Cell Nucleus

act(complex(GO:"protein phosphatase type 2A complex")) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

There is a significant decrease in total PP2A activity measured in AD cortical and hippocampal brain homogenates (Gong et al.,1993; Gong et al.,1995; Sontag et al.,2004b). PubMed:24653673

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Annotations
MeSH
Cerebral Cortex
MeSH
Hippocampus

complex(GO:"protein phosphatase type 2A complex") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

In contrast, “PP2A” expression levels are increased in AD astrocytes (Pei et al., 1997). PubMed:24653673

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Annotations
MeSH
Astrocytes

act(complex(GO:"protein phosphatase type 2A complex")) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Collectively, those studies point to a central role for PP2A dysfunction in AD pathogenesis PubMed:24653673

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act(complex(GO:"protein phosphatase type 2A complex")) association p(HGNC:PPP2CA) View Subject | View Object

Deficits in PP2A activity are in line with the reported down-regulation of PP2A catalytic C subunit at the gene (Loring et al.,2001), mRNA (Vogelsberg-Ragaglia et al.,2001) and protein (Sontag et al.,2004b) expression levels in AD. PubMed:24653673

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act(complex(GO:"protein phosphatase type 2A complex")) negativeCorrelation p(HGNC:ANP32A) View Subject | View Object

Up-regulation of I1 PP2A and I2 PP2A, and mislocalization and cleavage of I2 PP2A, could underlie the inactivation of PP2A in AD neocortical neurons (Tanimukai et al.,2005). PubMed:24653673

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Annotations
MeSH
Neocortex
MeSH
Alzheimer Disease

act(complex(GO:"protein phosphatase type 2A complex")) negativeCorrelation p(HGNC:SET) View Subject | View Object

Up-regulation of I1 PP2A and I2 PP2A, and mislocalization and cleavage of I2 PP2A, could underlie the inactivation of PP2A in AD neocortical neurons (Tanimukai et al.,2005). PubMed:24653673

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Annotations
MeSH
Neocortex
MeSH
Alzheimer Disease

act(complex(GO:"protein phosphatase type 2A complex")) negativeCorrelation p(HGNC:SET) View Subject | View Object

For instance, activated GSK3β has been reported to induce PP2A inactivation via several mechanisms: phosphorylation of PP2A on Tyr307 (Yao et al.,2011); demethylation of PP2A on Leu309 through inhibition of LCMT1 and up-regulation of PME1 (Yao et al.,2012); and accumulation of I2 PP2A (Liu et al.,2008a). PubMed:24653673

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act(complex(GO:"protein phosphatase type 2A complex")) negativeCorrelation p(HGNC:SET, frag("?")) View Subject | View Object

Up-regulation of I1 PP2A and I2 PP2A, and mislocalization and cleavage of I2 PP2A, could underlie the inactivation of PP2A in AD neocortical neurons (Tanimukai et al.,2005). PubMed:24653673

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Annotations
MeSH
Neocortex
MeSH
Alzheimer Disease

act(complex(GO:"protein phosphatase type 2A complex")) negativeCorrelation p(FPLX:PPP2, pmod(Ph, Tyr, 307)) View Subject | View Object

Decreased expression levels of PTPA in AD brain tissue may also lead to inactivation of PP2A by indirectly increasing levels of PP2A phosphorylated at the Tyr-307 site (Luo et al.,2013). PubMed:24653673

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Annotations
MeSH
Alzheimer Disease

act(complex(GO:"protein phosphatase type 2A complex")) decreases bp(GO:"neuron death") View Subject | View Object

Not surprisingly, inhibition of total cellular PP2A activity ultimately leads to neuronal cell death. PubMed:24653673

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act(complex(GO:"protein phosphatase type 2A complex")) increases act(p(HGNC:GSK3B)) View Subject | View Object

Specific PP2A inhibition has been proven to lead to in vivo deregulation of many major brain Ser/Thr kinases implicated in AD, including GSK3β (Wang et al., 2010; Louis et al., 2011), cdk5 (Louis et al., 2011; Kimura et al., 2013), extracellular signal- regulated kinase (ERK) and JNK (Kins et al., 2003). PubMed:24653673

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act(complex(GO:"protein phosphatase type 2A complex")) increases act(p(HGNC:CDK5)) View Subject | View Object

Specific PP2A inhibition has been proven to lead to in vivo deregulation of many major brain Ser/Thr kinases implicated in AD, including GSK3β (Wang et al., 2010; Louis et al., 2011), cdk5 (Louis et al., 2011; Kimura et al., 2013), extracellular signal- regulated kinase (ERK) and JNK (Kins et al., 2003). PubMed:24653673

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act(complex(GO:"protein phosphatase type 2A complex")) increases act(p(FPLX:ERK)) View Subject | View Object

Specific PP2A inhibition has been proven to lead to in vivo deregulation of many major brain Ser/Thr kinases implicated in AD, including GSK3β (Wang et al., 2010; Louis et al., 2011), cdk5 (Louis et al., 2011; Kimura et al., 2013), extracellular signal- regulated kinase (ERK) and JNK (Kins et al., 2003). PubMed:24653673

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act(complex(GO:"protein phosphatase type 2A complex")) increases act(p(FPLX:JNK)) View Subject | View Object

Specific PP2A inhibition has been proven to lead to in vivo deregulation of many major brain Ser/Thr kinases implicated in AD, including GSK3β (Wang et al., 2010; Louis et al., 2011), cdk5 (Louis et al., 2011; Kimura et al., 2013), extracellular signal- regulated kinase (ERK) and JNK (Kins et al., 2003). PubMed:24653673

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About

BEL Commons is developed and maintained in an academic capacity by Charles Tapley Hoyt and Daniel Domingo-Fernández at the Fraunhofer SCAI Department of Bioinformatics with support from the IMI project, AETIONOMY. It is built on top of PyBEL, an open source project. Please feel free to contact us here to give us feedback or report any issues. Also, see our Publishing Notes and Data Protection information.

If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.