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  3. PubMed:24653673

PubMed: 24653673

Title
Protein phosphatase 2A dysfunction in Alzheimer's disease.
Journal
Frontiers in molecular neuroscience
Volume
7
Issue
None
Pages
16
Date
2014-01-01
Authors
Sontag E | Sontag JM

Evidence 01f8338ad8
JSON

Like all methyltransferases,LCMT1 activity depends on the supply of the universal methyl donor, S-adenosylmethionine (SAM),and is inhibited by S-adenosylhomocysteine (SAH; Leulliot et al.,2004; Sontag et al.,2007).

a(CHEBI:"S-adenosyl-L-homocysteine") decreases act(p(HGNC:LCMT1)) View Subject | View Object

Appears in Networks:

a(CHEBI:"S-adenosyl-L-methionine") increases act(p(HGNC:LCMT1)) View Subject | View Object

Appears in Networks:

Evidence a2cb596853
JSON

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

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

Appears in Networks:

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

Appears in Networks:

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

Appears in Networks:

Evidence cac00646c8
JSON

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.

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

Appears in Networks:

a(CHEBI:"okadaic acid") increases complex(a(CHEBI:"okadaic acid"), p(HGNC:PPP2CA)) View Subject | View Object

Appears in Networks:

a(CHEBI:"okadaic acid") increases complex(a(CHEBI:"okadaic acid"), p(HGNC:PPP2CB)) View Subject | View Object

Appears in Networks:

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

Appears in Networks:

a(PUBCHEM:5311365) increases complex(a(PUBCHEM:5311365), p(HGNC:PPP2CA)) View Subject | View Object

Appears in Networks:

a(PUBCHEM:5311365) increases complex(a(PUBCHEM:5311365), p(HGNC:PPP2CB)) View Subject | View Object

Appears in Networks:

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

Appears in Networks:

a(PUBCHEM:6913994) increases complex(a(PUBCHEM:6913994), p(HGNC:PPP2CA)) View Subject | View Object

Appears in Networks:

a(PUBCHEM:6913994) increases complex(a(PUBCHEM:6913994), p(HGNC:PPP2CB)) View Subject | View Object

Appears in Networks:

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

Appears in Networks:

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

Appears in Networks:

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

Appears in Networks:

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

Appears in Networks:

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

Appears in Networks:

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

Appears in Networks:

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

Appears in Networks:

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

Appears in Networks:

p(HGNC:ANP32A) increases complex(p(HGNC:ANP32A), p(HGNC:PPP2CA)) View Subject | View Object

Appears in Networks:

p(HGNC:ANP32A) increases complex(p(HGNC:ANP32A), p(HGNC:PPP2CB)) View Subject | View Object

Appears in Networks:

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

Appears in Networks:

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

Appears in Networks:

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

Appears in Networks:

p(HGNC:SET) increases complex(p(HGNC:PPP2CA), p(HGNC:SET)) View Subject | View Object

Appears in Networks:

p(HGNC:SET) increases complex(p(HGNC:PPP2CB), p(HGNC:SET)) View Subject | View Object

Appears in Networks:

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

Appears in Networks:

Evidence 41fe1bbd06
JSON

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)

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

Appears in Networks:

a(CHEBI:"okadaic acid") decreases bp(GO:cognition) View Subject | View Object

Appears in Networks:

a(CHEBI:"okadaic acid") increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:

a(CHEBI:"okadaic acid") increases bp(HBP:amyloidogenesis) View Subject | View Object

Appears in Networks:

a(CHEBI:"okadaic acid") decreases a(GO:synapse) View Subject | View Object

Appears in Networks:

a(CHEBI:"okadaic acid") increases path(HBP:Neurodegeneration) View Subject | View Object

Appears in Networks:

Evidence 8ba872d0d0
JSON

Dietary folate and B-vitamin deficiency (Sontag et al.,2008; Nicolia et al.,2010) and elevated homocysteine levels (Sontag et al.,2007, 2013; Zhang et al.,2008) lead to down-regulation of PP2A methylation and concomitant phosphorylation of tau and/or APP in vivo

a(CHEBI:folates) decreases p(FPLX:PPP2, pmod(Me)) View Subject | View Object

Appears in Networks:

a(CHEBI:folates) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:

a(CHEBI:folates) increases p(HGNC:APP, pmod(Ph)) View Subject | View Object

Appears in Networks:

a(CHEBI:homocysteine) negativeCorrelation p(FPLX:PPP2, pmod(Me)) View Subject | View Object

Appears in Networks:

a(CHEBI:homocysteine) positiveCorrelation p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:

a(CHEBI:homocysteine) positiveCorrelation p(HGNC:APP, pmod(Ph)) View Subject | View Object

Appears in Networks:

p(FPLX:PPP2, pmod(Me)) negativeCorrelation a(CHEBI:homocysteine) View Subject | View Object

Appears in Networks:

p(FPLX:PPP2, pmod(Me)) negativeCorrelation p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:

p(FPLX:PPP2, pmod(Me)) negativeCorrelation p(HGNC:APP, pmod(Ph)) View Subject | View Object

Appears in Networks:

p(HGNC:APP, pmod(Ph)) positiveCorrelation a(CHEBI:homocysteine) View Subject | View Object

Appears in Networks:

p(HGNC:APP, pmod(Ph)) negativeCorrelation p(FPLX:PPP2, pmod(Me)) View Subject | View Object

Appears in Networks:

p(HGNC:MAPT, pmod(Ph)) positiveCorrelation a(CHEBI:homocysteine) View Subject | View Object

Appears in Networks:

p(HGNC:MAPT, pmod(Ph)) negativeCorrelation p(FPLX:PPP2, pmod(Me)) View Subject | View Object

Appears in Networks:

path(MESH:"Vitamin B Deficiency") decreases p(FPLX:PPP2, pmod(Me)) View Subject | View Object

Appears in Networks:

path(MESH:"Vitamin B Deficiency") increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:

path(MESH:"Vitamin B Deficiency") increases p(HGNC:APP, pmod(Ph)) View Subject | View Object

Appears in Networks:

Evidence 17e886549b
JSON

Apart from affecting tau phosphorylation, abnormal activation of GSK3β, cdk5, and ERK has been linked to cytoskeletal abnormalities (microtubules, neurofilaments), alterations in amyloid precursor protein (APP) phosphorylation and processing, impairment of neurogenesis, alterations in synaptic plasticity and induction of apoptotic processes (Reviewed in Crews and Masliah, 2010; Medina and Avila, 2013, 2014).

a(GO:"microtubule cytoskeleton") negativeCorrelation act(p(HGNC:GSK3B)) View Subject | View Object

Appears in Networks:

a(GO:"microtubule cytoskeleton") negativeCorrelation act(p(HGNC:CDK5)) View Subject | View Object

Appears in Networks:

a(GO:"microtubule cytoskeleton") negativeCorrelation act(p(FPLX:ERK)) View Subject | View Object

Appears in Networks:

a(GO:"neurofilament cytoskeleton") negativeCorrelation act(p(HGNC:GSK3B)) View Subject | View Object

Appears in Networks:

a(GO:"neurofilament cytoskeleton") negativeCorrelation act(p(HGNC:CDK5)) View Subject | View Object

Appears in Networks:

a(GO:"neurofilament cytoskeleton") negativeCorrelation act(p(FPLX:ERK)) View Subject | View Object

Appears in Networks:

bp(GO:"apoptotic process") positiveCorrelation act(p(HGNC:GSK3B)) View Subject | View Object

Appears in Networks:

bp(GO:"apoptotic process") positiveCorrelation act(p(HGNC:CDK5)) View Subject | View Object

Appears in Networks:

bp(GO:"apoptotic process") positiveCorrelation act(p(FPLX:ERK)) View Subject | View Object

Appears in Networks:

bp(GO:"negative regulation of synaptic plasticity") positiveCorrelation act(p(HGNC:GSK3B)) View Subject | View Object

Appears in Networks:

bp(GO:"negative regulation of synaptic plasticity") positiveCorrelation act(p(HGNC:CDK5)) View Subject | View Object

Appears in Networks:

bp(GO:"negative regulation of synaptic plasticity") positiveCorrelation act(p(FPLX:ERK)) View Subject | View Object

Appears in Networks:

bp(GO:neurogenesis) negativeCorrelation act(p(HGNC:GSK3B)) View Subject | View Object

Appears in Networks:

bp(GO:neurogenesis) negativeCorrelation act(p(HGNC:CDK5)) View Subject | View Object

Appears in Networks:

bp(GO:neurogenesis) negativeCorrelation act(p(FPLX:ERK)) View Subject | View Object

Appears in Networks:

bp(HBP:"APP processing") negativeCorrelation act(p(HGNC:GSK3B)) View Subject | View Object

Appears in Networks:

bp(HBP:"APP processing") negativeCorrelation act(p(HGNC:CDK5)) View Subject | View Object

Appears in Networks:

bp(HBP:"APP processing") negativeCorrelation act(p(FPLX:ERK)) View Subject | View Object

Appears in Networks:

act(p(HGNC:CDK5)) negativeCorrelation a(GO:"microtubule cytoskeleton") View Subject | View Object

Appears in Networks:

act(p(HGNC:CDK5)) negativeCorrelation a(GO:"neurofilament cytoskeleton") View Subject | View Object

Appears in Networks:

act(p(HGNC:CDK5)) negativeCorrelation p(HGNC:APP, pmod(Ph)) View Subject | View Object

Appears in Networks:

act(p(HGNC:CDK5)) negativeCorrelation bp(HBP:"APP processing") View Subject | View Object

Appears in Networks:

act(p(HGNC:CDK5)) negativeCorrelation bp(GO:neurogenesis) View Subject | View Object

Appears in Networks:

act(p(HGNC:CDK5)) positiveCorrelation bp(GO:"negative regulation of synaptic plasticity") View Subject | View Object

Appears in Networks:

act(p(HGNC:CDK5)) positiveCorrelation bp(GO:"apoptotic process") View Subject | View Object

Appears in Networks:

act(p(HGNC:GSK3B)) negativeCorrelation a(GO:"microtubule cytoskeleton") View Subject | View Object

Appears in Networks:

act(p(HGNC:GSK3B)) negativeCorrelation a(GO:"neurofilament cytoskeleton") View Subject | View Object

Appears in Networks:

act(p(HGNC:GSK3B)) negativeCorrelation p(HGNC:APP, pmod(Ph)) View Subject | View Object

Appears in Networks:

act(p(HGNC:GSK3B)) negativeCorrelation bp(HBP:"APP processing") View Subject | View Object

Appears in Networks:

act(p(HGNC:GSK3B)) negativeCorrelation bp(GO:neurogenesis) View Subject | View Object

Appears in Networks:

act(p(HGNC:GSK3B)) positiveCorrelation bp(GO:"negative regulation of synaptic plasticity") View Subject | View Object

Appears in Networks:

act(p(HGNC:GSK3B)) positiveCorrelation bp(GO:"apoptotic process") View Subject | View Object

Appears in Networks:

act(p(FPLX:ERK)) negativeCorrelation a(GO:"microtubule cytoskeleton") View Subject | View Object

Appears in Networks:

act(p(FPLX:ERK)) negativeCorrelation a(GO:"neurofilament cytoskeleton") View Subject | View Object

Appears in Networks:

act(p(FPLX:ERK)) negativeCorrelation p(HGNC:APP, pmod(Ph)) View Subject | View Object

Appears in Networks:

act(p(FPLX:ERK)) negativeCorrelation bp(HBP:"APP processing") View Subject | View Object

Appears in Networks:

act(p(FPLX:ERK)) negativeCorrelation bp(GO:neurogenesis) View Subject | View Object

Appears in Networks:

act(p(FPLX:ERK)) positiveCorrelation bp(GO:"negative regulation of synaptic plasticity") View Subject | View Object

Appears in Networks:

act(p(FPLX:ERK)) positiveCorrelation bp(GO:"apoptotic process") View Subject | View Object

Appears in Networks:

p(HGNC:APP, pmod(Ph)) negativeCorrelation act(p(HGNC:GSK3B)) View Subject | View Object

Appears in Networks:

p(HGNC:APP, pmod(Ph)) negativeCorrelation act(p(HGNC:CDK5)) View Subject | View Object

Appears in Networks:

p(HGNC:APP, pmod(Ph)) negativeCorrelation act(p(FPLX:ERK)) View Subject | View Object

Appears in Networks:

Evidence 31032b5788
JSON

Lastly, increased phosphorylation of PP2A at Tyr-307 has been found in P-tau-rich, tangle-bearing neurons from post-mortem brain (Liu et al.,2008b).

a(GO:"neurofibrillary tangle") association p(FPLX:PPP2, pmod(Me, Tyr, 307)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Neurons
MeSH
Alzheimer Disease

p(FPLX:PPP2, pmod(Me, Tyr, 307)) association a(GO:"neurofibrillary tangle") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Neurons
MeSH
Alzheimer Disease

p(FPLX:PPP2, pmod(Me, Tyr, 307)) association p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Neurons
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(Ph)) association p(FPLX:PPP2, pmod(Me, Tyr, 307)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Neurons
MeSH
Alzheimer Disease

Evidence e7910d74c5
JSON

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).

a(MESH:"Receptors, N-Methyl-D-Aspartate") association path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

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

Appears in Networks:

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

Appears in Networks:

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

Appears in Networks:

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

Appears in Networks:

p(HGNC:CDK5) association path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

p(HGNC:GRM5) association path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

p(HGNC:GSK3B) association path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") association p(HGNC:GSK3B) View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") association p(HGNC:CDK5) View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") association a(MESH:"Receptors, N-Methyl-D-Aspartate") View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") association p(HGNC:GRM5) View Subject | View Object

Appears in Networks:

Evidence 6e5dd87a77
JSON

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).

bp(GO:"insulin receptor signaling pathway") increases p(HGNC:PPP2CA, pmod(Ph, Tyr, 307)) View Subject | View Object

Appears in Networks:

bp(GO:"insulin receptor signaling pathway") increases p(HGNC:PPP2CB, pmod(Ph, Tyr, 307)) View Subject | View Object

Appears in Networks:

p(HGNC:EGFR) increases p(HGNC:PPP2CA, pmod(Ph, Tyr, 307)) View Subject | View Object

Appears in Networks:

p(HGNC:EGFR) increases p(HGNC:PPP2CB, pmod(Ph, Tyr, 307)) View Subject | View Object

Appears in Networks:

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

Appears in Networks:

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

Appears in Networks:

p(HGNC:SRC) increases p(HGNC:PPP2CA, pmod(Ph, Tyr, 307)) View Subject | View Object

Appears in Networks:

p(HGNC:SRC) increases p(HGNC:PPP2CB, pmod(Ph, Tyr, 307)) View Subject | View Object

Appears in Networks:

Evidence 3d947e23e2
JSON

The deregulation of PP2A methylation in AD is especially interesting, not only because it can lead to a loss of PP2A/Bα, a major tau regulator, but also because PP2A methylation state is intimately linked to the integrity of one-carbon metabolism, which regulates SAM supply (Reviewed in Fowler,2005).

bp(GO:"one-carbon metabolic process") association p(FPLX:PPP2, pmod(Me)) View Subject | View Object

Appears in Networks:

complex(p(HGNC:PPP2CA), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) positiveCorrelation p(FPLX:PPP2, pmod(Me)) View Subject | View Object

Appears in Networks:

complex(p(HGNC:PPP2CA), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

complex(p(HGNC:PPP2CB), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) positiveCorrelation p(FPLX:PPP2, pmod(Me)) View Subject | View Object

Appears in Networks:

complex(p(HGNC:PPP2CB), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

p(FPLX:PPP2, pmod(Me)) positiveCorrelation complex(p(HGNC:PPP2CA), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) View Subject | View Object

Appears in Networks:

p(FPLX:PPP2, pmod(Me)) positiveCorrelation complex(p(HGNC:PPP2CB), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) View Subject | View Object

Appears in Networks:

p(FPLX:PPP2, pmod(Me)) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

p(FPLX:PPP2, pmod(Me)) association bp(GO:"one-carbon metabolic process") View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation p(FPLX:PPP2, pmod(Me)) View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation complex(p(HGNC:PPP2CA), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation complex(p(HGNC:PPP2CB), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) View Subject | View Object

Appears in Networks:

Evidence 3da7ab127c
JSON

Remarkably, impairment of one-carbon metabolism in animal models can reproduce AD-like pathological features: accumulation of P-tau (Sontag et al.,2007; Zhang et al.,2008; Wei et al.,2011); enhanced amyloidogenesis (Pacheco-Quinto et al.,2006; Zhang et al.,2009; Zhuo et al.,2010; Zhuo and Pratico,2010); increased phosphorylation of APP at the regulatory Thr-668 site (Sontag et al.,2007; Zhang et al.,2009); increased sensitivity to amyloid toxicity (Kruman et al.,2002); and cognitive impairment (Bernardo et al.,2007; Wei et al.,2011; Rhodehouse et al., 2013).

bp(GO:"one-carbon metabolic process") decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:

bp(GO:"one-carbon metabolic process") decreases bp(HBP:amyloidogenesis) View Subject | View Object

Appears in Networks:

bp(GO:"one-carbon metabolic process") decreases p(HGNC:APP, pmod(Ph, Thr, 668)) View Subject | View Object

Appears in Networks:

bp(GO:"one-carbon metabolic process") decreases bp(GO:cognition) View Subject | View Object

Appears in Networks:

bp(GO:"one-carbon metabolic process") decreases act(a(CHEBI:"amyloid-beta")) View Subject | View Object

Appears in Networks:

Evidence 2e4e71d781
JSON

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

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

Appears in Networks:

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

Appears in Networks:

p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55") decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:

Evidence eb373ea99d
JSON

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).

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

Appears in Networks:

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

Appears in Networks:

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

Appears in Networks:

p(HGNC:SRC) increases p(HGNC:PPP2CA, pmod(Ph, Tyr, 307)) View Subject | View Object

Appears in Networks:

p(HGNC:SRC) increases p(HGNC:PPP2CB, pmod(Ph, Tyr, 307)) View Subject | View Object

Appears in Networks:

Evidence fa426c4e17
JSON

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).

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

Appears in Networks:

complex(p(HGNC:PPP2CA), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:

complex(p(HGNC:PPP2CB), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:

Evidence ac190ca450
JSON

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).

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

Appears in Networks:
Annotations
MeSH
Cell Nucleus

p(HGNC:LCMT1) increases p(HGNC:PPP2CA, pmod(Me, Leu, 309)) View Subject | View Object

Appears in Networks:

p(HGNC:LCMT1) increases p(HGNC:PPP2CB, pmod(Me, Leu, 309)) View Subject | View Object

Appears in Networks:

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

Appears in Networks:

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

Appears in Networks:
Annotations
MeSH
Cell Nucleus

Evidence 95b1768c68
JSON

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).

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

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
MeSH
Hippocampus

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

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
MeSH
Hippocampus

Evidence 47529f9231
JSON

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

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

Appears in Networks:
Annotations
MeSH
Astrocytes

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

Appears in Networks:
Annotations
MeSH
Astrocytes

Evidence c08aea4bbd
JSON

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

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

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

Appears in Networks:

Evidence 20e0110d4b
JSON

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.

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

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

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

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p(HGNC:PPP2CA) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

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

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p(HGNC:PPP2CB) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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g(HGNC:PPP2CA) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

g(HGNC:PPP2CB) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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path(MESH:"Alzheimer Disease") negativeCorrelation g(HGNC:PPP2CA) View Subject | View Object

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path(MESH:"Alzheimer Disease") negativeCorrelation r(HGNC:PPP2CA) View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation p(HGNC:PPP2CA) View Subject | View Object

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path(MESH:"Alzheimer Disease") negativeCorrelation g(HGNC:PPP2CB) View Subject | View Object

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path(MESH:"Alzheimer Disease") negativeCorrelation r(HGNC:PPP2CB) View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation p(HGNC:PPP2CB) View Subject | View Object

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r(HGNC:PPP2CA) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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r(HGNC:PPP2CB) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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Evidence 9a0bd39371
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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).

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

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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

Appears in Networks:
Annotations
MeSH
Neocortex
MeSH
Alzheimer Disease

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

Appears in Networks:
Annotations
MeSH
Neocortex
MeSH
Alzheimer Disease

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

Appears in Networks:
Annotations
MeSH
Neocortex
MeSH
Alzheimer Disease

p(HGNC:ANP32A) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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

Appears in Networks:
Annotations
MeSH
Neocortex
MeSH
Alzheimer Disease

p(HGNC:SET) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Neocortex
MeSH
Alzheimer Disease

p(HGNC:SET, frag("?")) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Neocortex
MeSH
Alzheimer Disease

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

Appears in Networks:
Annotations
MeSH
Neocortex
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:ANP32A) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Neocortex
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:SET) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Neocortex
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:SET, frag("?")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Neocortex
MeSH
Alzheimer Disease

Evidence ea6bbf9638
JSON

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).

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

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

Appears in Networks:

act(p(HGNC:GSK3B)) increases p(FPLX:PPP2, pmod(Ph, Tyr, 307)) View Subject | View Object

Appears in Networks:

act(p(HGNC:GSK3B)) decreases p(HGNC:PPP2CA, pmod(Me, Leu, 309)) View Subject | View Object

Appears in Networks:

act(p(HGNC:GSK3B)) decreases p(HGNC:PPP2CB, pmod(Me, Leu, 309)) View Subject | View Object

Appears in Networks:

act(p(HGNC:GSK3B)) decreases act(p(HGNC:LCMT1)) View Subject | View Object

Appears in Networks:

act(p(HGNC:GSK3B)) increases act(p(HGNC:PPME1)) View Subject | View Object

Appears in Networks:

act(p(HGNC:GSK3B)) increases p(HGNC:SET) View Subject | View Object

Appears in Networks:

p(HGNC:LCMT1) increases p(HGNC:PPP2CA, pmod(Me, Leu, 309)) View Subject | View Object

Appears in Networks:

p(HGNC:LCMT1) increases p(HGNC:PPP2CB, pmod(Me, Leu, 309)) View Subject | View Object

Appears in Networks:

act(p(HGNC:PPME1)) decreases p(HGNC:PPP2CA, pmod(Me, Leu, 309)) View Subject | View Object

Appears in Networks:

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

Appears in Networks:

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

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

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

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Evidence 8199da2ef5
JSON

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).

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

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HGNC:PTPA) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

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

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HGNC:PTPA) decreases p(FPLX:PPP2, pmod(Ph, Tyr, 307)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

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

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") negativeCorrelation p(HGNC:PTPA) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

Evidence 82859fc8e4
JSON

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

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

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Evidence e8a197394d
JSON

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).

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

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

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

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

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Evidence bbe1f116af
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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).

deg(p(HGNC:PPP2CA)) positiveCorrelation p(HGNC:IGBP1, frag("?")) View Subject | View Object

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Annotations
MeSH
Alzheimer Disease

deg(p(HGNC:PPP2CB)) positiveCorrelation p(HGNC:IGBP1, frag("?")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(FPLX:CAPN) increases p(HGNC:IGBP1, frag("?")) View Subject | View Object

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

Appears in Networks:

p(HGNC:IGBP1, frag("?")) positiveCorrelation deg(p(HGNC:PPP2CA)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HGNC:IGBP1, frag("?")) positiveCorrelation deg(p(HGNC:PPP2CB)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

Evidence c806c33946
JSON

Knock-down of PP2A catalytic subunit (Kins et al.,2001) or PP2A B’δ (or PPP2R5D) regulatory subunit (Louis et al.,2011), and expression of the methylation-site L309A C subunit mutant (Schild et al.,2006) all induce AD-like tau phosphorylation in transgenic mice

p(HGNC:PPP2CA) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

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p(HGNC:PPP2CB) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:

p(HGNC:PPP2CA, var("p.Leu309Ala")) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

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p(HGNC:PPP2CB, var("p.Leu309Ala")) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

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p(HGNC:PPP2R5D) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

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Evidence d0edbf67f7
JSON

Conversely, decreased PP2A methylation and PP2A/Bα levels in AD will disrupt normal PP2A-tau interactions (Sontag et al., 2007), thereby preventing PP2A-mediated tau dephosphorylation while allowing for enhanced binding of Fyn kinase or other regulators to the tau proteins.

complex(p(HGNC:FYN), p(HGNC:MAPT)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

complex(p(HGNC:MAPT), p(HGNC:PPP2CA), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:

complex(p(HGNC:MAPT), p(HGNC:PPP2CA), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

complex(p(HGNC:MAPT), p(HGNC:PPP2CB), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:

complex(p(HGNC:MAPT), p(HGNC:PPP2CB), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

complex(p(HGNC:PPP2CA), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) increases complex(p(HGNC:MAPT), p(HGNC:PPP2CA), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) View Subject | View Object

Appears in Networks:

complex(p(HGNC:PPP2CA), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

complex(p(HGNC:PPP2CB), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) increases complex(p(HGNC:MAPT), p(HGNC:PPP2CB), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) View Subject | View Object

Appears in Networks:

complex(p(HGNC:PPP2CB), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

p(FPLX:PPP2, pmod(Me)) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

p(HGNC:MAPT, pmod(Ph)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation p(FPLX:PPP2, pmod(Me)) View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation complex(p(HGNC:PPP2CA), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation complex(p(HGNC:PPP2CB), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation complex(p(HGNC:MAPT), p(HGNC:PPP2CA), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation complex(p(HGNC:MAPT), p(HGNC:PPP2CB), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation complex(p(HGNC:FYN), p(HGNC:MAPT)) View Subject | View Object

Appears in Networks:

Evidence 2574a6c607
JSON

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

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

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

Appears in Networks:

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

Appears in Networks:

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

Appears in Networks:

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

Appears in Networks:

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

Appears in Networks:

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

Appears in Networks:

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

Appears in Networks:

Evidence 7592d461f8
JSON

Proteinphosphatase 2A catalytic subunit is uniquely methylated on Leu-309 by the dedicated leucine carboxyl methyltransferase-1 (LCMT-1; Lee et al.,1996; De Baere et al.,1999).

p(HGNC:LCMT1) increases p(HGNC:PPP2CA, pmod(Me, Leu, 309)) View Subject | View Object

Appears in Networks:

p(HGNC:LCMT1) increases p(HGNC:PPP2CB, pmod(Me, Leu, 309)) View Subject | View Object

Appears in Networks:

Evidence 88af2edaf9
JSON

Significantly, downregulation of LCMT1 expression leads to a significant decrease of PP2A methylation and concomitant loss of PP2A holoenzymes containing the regulatory Bα (or PPP2R2A) subunit (PP2A/Bα; Lee and Pallas,2007; Sontag et al.,2008; MacKay et al.,2013).

p(HGNC:LCMT1) increases p(HGNC:PPP2CA, pmod(Me, Leu, 309)) View Subject | View Object

Appears in Networks:

p(HGNC:LCMT1) increases p(HGNC:PPP2CB, pmod(Me, Leu, 309)) View Subject | View Object

Appears in Networks:

p(HGNC:PPP2CA, pmod(Me, Leu, 309)) increases complex(p(HGNC:PPP2CA), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) View Subject | View Object

Appears in Networks:

p(HGNC:PPP2CB, pmod(Me, Leu, 309)) increases complex(p(HGNC:PPP2CB), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) View Subject | View Object

Appears in Networks:

Evidence 7030f32018
JSON

Significantly, down-regulation of LCMT1 protein expression parallels the deficits in PP2A methylation observed in AD (Sontag et al.,2004a).

p(HGNC:LCMT1) increases p(FPLX:PPP2, pmod(Me)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(FPLX:PPP2, pmod(Me)) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") negativeCorrelation p(FPLX:PPP2, pmod(Me)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

Evidence 92dad743e2
JSON

It is noteworthy that PP2A/Bα can directly bind to tau via a domain encompassing the microtubule-binding of tau; this interaction maximizes the efficiency of tau dephosphorylation by PP2A (Sontag et al.,1999; Xu et al.,2008; Figure 3A).

complex(p(HGNC:MAPT), p(HGNC:PPP2CA), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:

complex(p(HGNC:MAPT), p(HGNC:PPP2CB), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:

complex(p(HGNC:PPP2CA), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) increases complex(p(HGNC:MAPT), p(HGNC:PPP2CA), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) View Subject | View Object

Appears in Networks:

complex(p(HGNC:PPP2CB), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) increases complex(p(HGNC:MAPT), p(HGNC:PPP2CB), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) View Subject | View Object

Appears in Networks:

Evidence 8d73478a75
JSON

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).

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

Appears in Networks:

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

Appears in Networks:

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

Appears in Networks:

Evidence 265cb8d229
JSON

More specifically, decreased expression levels of PP2A regulatory Bγ (or PPP2R2C) and B’ε (or PPP2R5E) subunit mRNAs in the hippocampus (Vogelsberg-Ragaglia et al.,2001), and cortical Bα subunit (Sontag et al.,2004b) have been reported in AD.

p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55") negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

path(MESH:"Alzheimer Disease") negativeCorrelation r(HGNC:PPP2R2C) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus

path(MESH:"Alzheimer Disease") negativeCorrelation r(HGNC:PPP2R5E) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus

path(MESH:"Alzheimer Disease") negativeCorrelation p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

r(HGNC:PPP2R2C) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus

r(HGNC:PPP2R5E) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus

Evidence 64507e4b37
JSON

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).

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

Appears in Networks:

p(HGNC:PPME1) increases complex(p(HGNC:PPME1), p(HGNC:PPP2CA)) View Subject | View Object

Appears in Networks:

p(HGNC:PPME1) increases complex(p(HGNC:PPME1), p(HGNC:PPP2CB)) View Subject | View Object

Appears in Networks:

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

Appears in Networks:

Evidence 21099827c7
JSON

Of particular relevance to the Alzheimer’s disease (AD) field, PP2A/Bα holoenzymes can directly bind to the microtubule-associated protein tau (Sontag et al.,1999, 2012; Xu et al.,2008).

complex(p(HGNC:PPP2CA), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) increases complex(p(HGNC:MAPT), p(HGNC:PPP2CA), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

complex(p(HGNC:PPP2CB), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) increases complex(p(HGNC:MAPT), p(HGNC:PPP2CB), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

Evidence a16b445cf3
JSON

Notably, the loss of neuronal PP2A/Bα holoenzymes correlates with the down-regulation of PP2A methylation and severity of phosphorylated tau (P-tau) pathology in AD-affected brain regions (Sontag et al.,2004 a,b).

complex(p(HGNC:PPP2CA), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) positiveCorrelation p(FPLX:PPP2, pmod(Me)) View Subject | View Object

Appears in Networks:

complex(p(HGNC:PPP2CB), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) positiveCorrelation p(FPLX:PPP2, pmod(Me)) View Subject | View Object

Appears in Networks:

complex(p(HGNC:PPP2CB), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) negativeCorrelation path(MESH:Tauopathies) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(FPLX:PPP2, pmod(Me)) positiveCorrelation complex(p(HGNC:PPP2CA), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) View Subject | View Object

Appears in Networks:

p(FPLX:PPP2, pmod(Me)) positiveCorrelation complex(p(HGNC:PPP2CB), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) View Subject | View Object

Appears in Networks:

path(MESH:Tauopathies) negativeCorrelation complex(p(HGNC:PPP2CB), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

Evidence 1d363f7fb6
JSON

As described earlier, it is especially significant that the biogenesis of PP2A/Bα holoenzymes is intimately related to the methylation state of PP2A

complex(p(HGNC:PPP2CA), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) association p(FPLX:PPP2, pmod(Me)) View Subject | View Object

Appears in Networks:

complex(p(HGNC:PPP2CB), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) association p(FPLX:PPP2, pmod(Me)) View Subject | View Object

Appears in Networks:

p(FPLX:PPP2, pmod(Me)) association complex(p(HGNC:PPP2CA), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) View Subject | View Object

Appears in Networks:

p(FPLX:PPP2, pmod(Me)) association complex(p(HGNC:PPP2CB), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) View Subject | View Object

Appears in Networks:

Evidence 1dd387e30d
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Specific inhibition of PP2A/Bα is associated with enhanced tau phosphorylation at many AD-like phospho epitopes, and subsequent inability of tau to bind to and stabilize microtubules (Sontag et al., 1996).

complex(p(HGNC:PPP2CA), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:

complex(p(HGNC:PPP2CA), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) increases complex(a(GO:microtubule), p(HGNC:MAPT)) View Subject | View Object

Appears in Networks:

complex(p(HGNC:PPP2CB), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:

complex(p(HGNC:PPP2CB), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) increases complex(a(GO:microtubule), p(HGNC:MAPT)) View Subject | View Object

Appears in Networks:

Evidence f163e3b328
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Deregulation of PP2A/Bα alone also affects microtubule stability (Nunbhakdi-Craig et al., 2007) and neurite outgrowth (Sontag et al.,2010) in neuroblastoma cells

complex(p(HGNC:PPP2CA), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) regulates a(GO:microtubule) View Subject | View Object

Appears in Networks:

complex(p(HGNC:PPP2CA), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) regulates bp(MESH:"Neuronal Outgrowth") View Subject | View Object

Appears in Networks:

complex(p(HGNC:PPP2CB), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) regulates a(GO:microtubule) View Subject | View Object

Appears in Networks:

complex(p(HGNC:PPP2CB), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) regulates bp(MESH:"Neuronal Outgrowth") View Subject | View Object

Appears in Networks:

Evidence 6863844948
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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).

p(FPLX:PKA) increases p(HGNC:PPP2R5A, pmod(Ph, Ser)) View Subject | View Object

Appears in Networks:

p(FPLX:PKA) increases p(HGNC:PPP2R5D, pmod(Ph, Ser)) View Subject | View Object

Appears in Networks:

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

Appears in Networks:

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

Appears in Networks:

Evidence 382e018206
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In cultured cells, deregulation of PP2A methylation also affects APP processing (Sontag et al.,2007), neurite outgrowth (Sontag et al.,2010) and tau distribution (Sontag et al.,2013).

p(FPLX:PPP2, pmod(Me)) regulates bp(HBP:"APP processing") View Subject | View Object

Appears in Networks:

p(FPLX:PPP2, pmod(Me)) regulates bp(MESH:"Neuronal Outgrowth") View Subject | View Object

Appears in Networks:

p(FPLX:PPP2, pmod(Me)) regulates p(HGNC:MAPT) View Subject | View Object

Appears in Networks:

Evidence 12880bd5d3
JSON

Notably, tau missense mutations found in frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17; Goedert et al.,2000) and AD-mimicking tau phosphorylation in proline-rich motifs (Eidenmuller et al.,2001) inhibit the association of tau with PP2A (Figure3B).

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

Appears in Networks:

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

Appears in Networks:

Evidence 798755080b
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Phosphorylation of the Thr-231 residue in this motif markedly decreases the affinity of tau for PP2A.

p(HGNC:MAPT, pmod(Ph, Thr, 231)) decreases complex(a(GO:"protein phosphatase type 2A complex"), p(HGNC:MAPT)) View Subject | View Object

Appears in Networks:

Evidence aaaafb0da8
JSON

This is potentially physiologically significant since phosphorylation of tau at Thr-231, a target site for ERK2, GSK3β, and cdk5, occurs early in AD and can further inhibit the ability of PP2A/Bα to dephosphorylate other major AD-tau phosphoepitopes (Landrieu et al.,2011).

p(HGNC:MAPT, pmod(Ph, Thr, 231)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

p(HGNC:MAPT, pmod(Ph, Thr, 231)) decreases act(complex(p(HGNC:PPP2CA), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55"))) View Subject | View Object

Appears in Networks:

p(HGNC:MAPT, pmod(Ph, Thr, 231)) decreases act(complex(p(HGNC:PPP2CB), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55"))) View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Thr, 231)) View Subject | View Object

Appears in Networks:

Evidence d7aab79651
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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).

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

Appears in Networks:
Annotations
MeSH
Endothelial Cells

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

Appears in Networks:

Evidence d3b5b19c60
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Methylation is thought to play a critical role in the biogenesis of PP2A holoenzymes.

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

Appears in Networks:

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

Appears in Networks:

Evidence e650d877cc
JSON

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).

p(HGNC:PPP2R1A, pmod(Ph, Ser), pmod(Ph, Thr)) decreases complex(p(HGNC:PPP2CA), p(HGNC:PPP2R1A)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Heart

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

Appears in Networks:
Annotations
MeSH
Heart

p(HGNC:PPP2R1B, pmod(Ph, Ser), pmod(Ph, Thr)) decreases complex(p(HGNC:PPP2CB), p(HGNC:PPP2R1A)) View Subject | View Object

Appears in Networks:
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

Appears in Networks:
Annotations
MeSH
Heart

Evidence 0013f2c550
JSON

Moreover, expression of an I2 PP2A fragment can recapitulate AD-like pathology in rat brain (Wang et al.,2010).

p(HGNC:SET, frag("?")) increases path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

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.