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p(HGNC:MAPT, pmod(Ph, Ser, 356))

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Entity

Name
MAPT
Namespace
hgnc
Namespace Version
20180906
Namespace URL
https://raw.githubusercontent.com/pharmacome/terminology/b46b65c3da259b6e86026514dfececab7c22a11b/external/hgnc-names.belns

Appears in Networks 6

Multivalent cross-linking of actin filaments and microtubules through the microtubule-associated protein Tau v1.0.0

Tau Protein Hyperphosphorylation and Aggregation in Alzheimer’s Disease and Other Tauopathies, and Possible Neuroprotective Strategies v1.0.0

Tau Biochemistry v1.2.5

Tau Biochemistry Section of NESTOR

TAU and Interaction Partners v1.2.5

TAU Interactions Section of NESTOR

Tau Modifications v1.9.5

Tau Modifications Sections of NESTOR

Pathological missorting of endogenous MAPT/Tau in neurons caused by failure of protein degradation systems v1.0.0

In-Edges 12

p(HGNC:MAPT) hasVariant p(HGNC:MAPT, pmod(Ph, Ser, 356)) View Subject | View Object

Appears in Networks:

p(HGNC:MARK2) increases p(HGNC:MAPT, pmod(Ph, Ser, 356)) View Subject | View Object

We therefore phosphorylated full-length Tau by MARK2. The downfield chemical shift of phosphorylated residues (Fig. 4a) is in agreement with previous reports and confirms phosphorylation at S262, S293, S305, S324, S356, and S416 PubMed:29215007

Appears in Networks:
Annotations
Confidence
High

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 356)) View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HGNC:CDC37) positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 356)) View Subject | View Object

Quantification of the Western blot showed that Cdc37 knockdown reduced phospho-Thr-231, phospho-Ser-199/Ser-202, phospho-Ser-396/Ser-404, and phospho-Ser-262/Ser-356 tau. PubMed:21367866

Appears in Networks:

p(HGNC:MAPT, pmod(HBP:"O-GlcNAcylation")) positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 356)) View Subject | View Object

Acute treatment of rTg4510 mice with an O-GlcNAcase inhibitor transiently reduced tau phosphorylation at epitopes implicated in tau pathology. More importantly, long-term inhibitor treatment strongly increased tau O-GlcNAcylation, reduced the number of dystrophic neurons, and protected against the formation of pathological tau species without altering the phosphorylation of non-pathological tau. PubMed:22833681

Appears in Networks:

act(p(HGNC:MARK2), ma(kin)) directlyIncreases p(HGNC:MAPT, pmod(Ph, Ser, 356)) View Subject | View Object

While residues Ser-262, Ser-324, and Ser-356 were completely phosphorylated, Ser-293 in the second repeat was only 84% phosphorylated (Table 1). Furthermore, four non-KXGS phosphorylation sites were detected, two within the repeat domain (Ser-305 in R2 and Ser-352 in R4) and two more at the C-terminus (Ser-413 and Ser-416) (Figure 1B,C). Of these, Ser-305 was 66% phosphorylated and Ser-352, Ser-413, and Ser-416 were ∼45−58% phosphorylated (Table 1). Using wild-type MARK2cat at 25 °C and pH 6.8, the same phosphorylation sites were observed. The three primary sites, Ser-262, Ser-324, and Ser-356, were still completely phosphorylated. PubMed:24251416

Appears in Networks:

act(p(INTERPRO:"Kinase associated domain 1 (KA1)"), ma(kin)) positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 356)) View Subject | View Object

We first confirmed that expression of an MKI-GFP fusion protein in rat hippocampal neurons effectively attenuated MARK4-mediated phosphorylation of both endogenous tau (Fig. 3A) and transfected human tau at the 12E8 sites (Fig. 3B). Phosphorylation of tau at the PHF-1 site was also reduced by MKI (Fig. 3A). It is possible that the PHF-1 site is also targeted by PAR-1/MARKs in vivo, or that the phosphorylation of tau at the 12E8 sites is a prerequisite for PHF-1 site phosphorylation, as the 12E8 sites were previously shown to be required for tau phosphorylation at other sites PubMed:22156579

Appears in Networks:

a(CHEBI:epoxomicin) positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 356)) View Subject | View Object

Missorted dendritic MAPT showed phosphorylation mainly at the 12E8 sites upon treatment with either the autophagy inhibitor wortmannin (Fig. 4B; 57.2±9.4% dendrites) or the proteasomal inhibitor epoxomicin (Fig. 4C, 62.9±7.4% dendrites) (Fig. 4A-C, quantification in Fig. 4D), but not at the AT8 and the PHF1 (p-S396/p-S404) sites (Fig. S5, Fig 4D). PubMed:30145931

Appears in Networks:
Annotations
MeSH
Dendrites

a(CHEBI:wortmannin) positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 356)) View Subject | View Object

Missorted dendritic MAPT showed phosphorylation mainly at the 12E8 sites upon treatment with either the autophagy inhibitor wortmannin (Fig. 4B; 57.2±9.4% dendrites) or the proteasomal inhibitor epoxomicin (Fig. 4C, 62.9±7.4% dendrites) (Fig. 4A-C, quantification in Fig. 4D), but not at the AT8 and the PHF1 (p-S396/p-S404) sites (Fig. S5, Fig 4D). PubMed:30145931

Appears in Networks:
Annotations
MeSH
Dendrites

a(HBP:"amyloid-beta oligomers") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 356)) View Subject | View Object

In addition, it has been reported that in cultured neurons, Aβ oligomers induce MAPT missorting into the somatodendritic compartment, and the missorted MAPT is phosphorylated mainly at the 12E8 (p-S262/p-S356) and AT8 (p-S202/p-T205) sites [6]. PubMed:30145931

Appears in Networks:
Annotations
MeSH
Dendrites

bp(GO:autophagy) increases deg(p(HGNC:MAPT, pmod(Ph, Ser, 356))) View Subject | View Object

Thus, the dendritic and axonal MAPT are differentially phosphorylated. Based on this observation, we can conclude that the dendritic MAPT degraded by autophagy or proteasomal pathways is phosphorylated mainly at the 12E8 site. PubMed:30145931

Appears in Networks:
Annotations
MeSH
Dendrites

act(p(FPLX:Proteasome)) increases deg(p(HGNC:MAPT, pmod(Ph, Ser, 356))) View Subject | View Object

Thus, the dendritic and axonal MAPT are differentially phosphorylated. Based on this observation, we can conclude that the dendritic MAPT degraded by autophagy or proteasomal pathways is phosphorylated mainly at the 12E8 site. PubMed:30145931

Appears in Networks:
Annotations
MeSH
Dendrites

Out-Edges 12

p(HGNC:MAPT, pmod(Ph, Ser, 356)) decreases complex(a(GO:"filamentous actin"), p(HGNC:MAPT)) View Subject | View Object

The NMR experiments demonstrate that MARK2- phosphorylation of Tau attenuates its binding to F-actin. Consistent with a reduced affinity, MARK2-phosphorylated Tau failed in bundling actin filaments (Fig. 4e) PubMed:29215007

Appears in Networks:
Annotations
Confidence
High

p(HGNC:MAPT, pmod(Ph, Ser, 356)) decreases bp(GO:"actin filament bundle assembly") View Subject | View Object

The NMR experiments demonstrate that MARK2- phosphorylation of Tau attenuates its binding to F-actin. Consistent with a reduced affinity, MARK2-phosphorylated Tau failed in bundling actin filaments (Fig. 4e) PubMed:29215007

Appears in Networks:
Annotations
Confidence
High

p(HGNC:MAPT, pmod(Ph, Ser, 356)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(Ph, Ser, 356)) decreases complex(p(HGNC:MAPT), p(HGNCGENEFAMILY:Tubulins)) View Subject | View Object

The lysine-isoleucine-glycineserine motif (KIGS) or lysine-cysteineglycine-serine motif (KCGS) motifs in the repeat domain (S262, S293, S324, S356) can be phosphorylated by MARK, PKA, SAD kinases, CaMKII and p70S6K, which strongly reduces the tau microtubule interactions (36, 74, 96), [note that phosphorylation at these sites also inhibits tau aggregation, illustrating an analogous role for the repeat domain in the physiological and pathological functions of tau (106)]. PubMed:17493042

Appears in Networks:
Annotations
Uberon
brain

p(HGNC:MAPT, pmod(Ph, Ser, 356)) decreases bp(GO:"neurofibrillary tangle assembly") View Subject | View Object

The lysine-isoleucine-glycineserine motif (KIGS) or lysine-cysteineglycine-serine motif (KCGS) motifs in the repeat domain (S262, S293, S324, S356) can be phosphorylated by MARK, PKA, SAD kinases, CaMKII and p70S6K, which strongly reduces the tau microtubule interactions (36, 74, 96), [note that phosphorylation at these sites also inhibits tau aggregation, illustrating an analogous role for the repeat domain in the physiological and pathological functions of tau (106)]. PubMed:17493042

Appears in Networks:
Annotations
Uberon
brain

p(HGNC:MAPT, pmod(Ph, Ser, 356)) positiveCorrelation p(HGNC:CDC37) View Subject | View Object

Quantification of the Western blot showed that Cdc37 knockdown reduced phospho-Thr-231, phospho-Ser-199/Ser-202, phospho-Ser-396/Ser-404, and phospho-Ser-262/Ser-356 tau. PubMed:21367866

Appears in Networks:

p(HGNC:MAPT, pmod(Ph, Ser, 356)) positiveCorrelation act(p(INTERPRO:"Kinase associated domain 1 (KA1)"), ma(kin)) View Subject | View Object

We first confirmed that expression of an MKI-GFP fusion protein in rat hippocampal neurons effectively attenuated MARK4-mediated phosphorylation of both endogenous tau (Fig. 3A) and transfected human tau at the 12E8 sites (Fig. 3B). Phosphorylation of tau at the PHF-1 site was also reduced by MKI (Fig. 3A). It is possible that the PHF-1 site is also targeted by PAR-1/MARKs in vivo, or that the phosphorylation of tau at the 12E8 sites is a prerequisite for PHF-1 site phosphorylation, as the 12E8 sites were previously shown to be required for tau phosphorylation at other sites PubMed:22156579

Appears in Networks:

p(HGNC:MAPT, pmod(Ph, Ser, 356)) partOf a(HBP:"Tau epitope, 12E8") View Subject | View Object

Appears in Networks:

p(HGNC:MAPT, pmod(Ph, Ser, 356)) positiveCorrelation p(HGNC:MAPT, pmod(HBP:"O-GlcNAcylation")) View Subject | View Object

Acute treatment of rTg4510 mice with an O-GlcNAcase inhibitor transiently reduced tau phosphorylation at epitopes implicated in tau pathology. More importantly, long-term inhibitor treatment strongly increased tau O-GlcNAcylation, reduced the number of dystrophic neurons, and protected against the formation of pathological tau species without altering the phosphorylation of non-pathological tau. PubMed:22833681

Appears in Networks:

p(HGNC:MAPT, pmod(Ph, Ser, 356)) positiveCorrelation a(HBP:"amyloid-beta oligomers") View Subject | View Object

In addition, it has been reported that in cultured neurons, Aβ oligomers induce MAPT missorting into the somatodendritic compartment, and the missorted MAPT is phosphorylated mainly at the 12E8 (p-S262/p-S356) and AT8 (p-S202/p-T205) sites [6]. PubMed:30145931

Appears in Networks:
Annotations
MeSH
Dendrites

p(HGNC:MAPT, pmod(Ph, Ser, 356)) positiveCorrelation a(CHEBI:wortmannin) View Subject | View Object

Missorted dendritic MAPT showed phosphorylation mainly at the 12E8 sites upon treatment with either the autophagy inhibitor wortmannin (Fig. 4B; 57.2±9.4% dendrites) or the proteasomal inhibitor epoxomicin (Fig. 4C, 62.9±7.4% dendrites) (Fig. 4A-C, quantification in Fig. 4D), but not at the AT8 and the PHF1 (p-S396/p-S404) sites (Fig. S5, Fig 4D). PubMed:30145931

Appears in Networks:
Annotations
MeSH
Dendrites

p(HGNC:MAPT, pmod(Ph, Ser, 356)) positiveCorrelation a(CHEBI:epoxomicin) View Subject | View Object

Missorted dendritic MAPT showed phosphorylation mainly at the 12E8 sites upon treatment with either the autophagy inhibitor wortmannin (Fig. 4B; 57.2±9.4% dendrites) or the proteasomal inhibitor epoxomicin (Fig. 4C, 62.9±7.4% dendrites) (Fig. 4A-C, quantification in Fig. 4D), but not at the AT8 and the PHF1 (p-S396/p-S404) sites (Fig. S5, Fig 4D). PubMed:30145931

Appears in Networks:
Annotations
MeSH
Dendrites

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