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Appears in Networks 12

In-Edges 44

act(p(HGNC:MARK2), ma(kin)) increases p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

An important class of kinases that phosphorylate Tau at S262 and the other KXGS motifs in the repeat domain are the microtubule-associated protein/microtubule affinity-regulating kinases (MARKs) PubMed:29215007

p(HGNC:MARK2) increases p(HGNC:MAPT, pmod(Ph, Ser, 262)) 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

a(CHEBI:"amyloid-beta polypeptide 42") increases p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

Interestingly, tau phosphor- ylation, which was detected by PHF-1 (Ser 396/404), CP13 (Ser 202) and 12E8 (Ser 262) antibodies, was also increased by Ab42 PubMed:22419736

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 262)) 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

p(HGNC:CDC37) positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 262)) 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

a(CHEBI:staurosporine) decreases p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

Several kinases such as microtubule-affinity regulating kinase (MARK), protein kinase A, calcium calmodulin kinase II, and checkpoint kinase 2 are known to phosphorylate tau on Ser(262) in vitro. In this study, we took advantage of the in situ proximity ligation assay to investigate the role of MARK2, one of the four MARK isoforms, in AD. We demonstrate that MARK2 interacts with tau and phosphorylates tau at Ser(262) in stably transfected NIH/3T3 cells expressing human recombinant tau. Staurosporine, a protein kinase inhibitor, significantly reduced the interaction between MARK2 and tau, and also phosphorylation of tau at Ser(262). PubMed:23001711

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a(HBP:"granulovacuolar degeneration") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

Immunohistochemical analyses using isoform-selective antibodies demonstrated that MARK4 in a phosphorylated form colocalizes with p-tau Ser262 in granulovacuolar degeneration bodies (GVDs) that progressively accumulate in AD. PubMed:11943212

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Annotations
Disease Ontology (DO)
Alzheimer's disease

a(HBP:Neurodegeneration) positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

Using transgenic Drosophila expressing human tau, we found that RNAi-mediated knockdown of milton or Miro, an adaptor protein essential for axonal transport of mitochondria, enhanced human tau-induced neurodegeneration. Tau phosphorylation at an AD-related site Ser262 increased with knockdown of milton or Miro; and partitioning defective-1 (PAR-1), the Drosophila homolog of mammalian microtubule affinity-regulating kinase, mediated this increase of tau phosphorylation. Tau phosphorylation at Ser262 has been reported to promote tau detachment from microtubules, and we found that the levels of microtubule-unbound free tau increased by milton knockdown. Blocking tau phosphorylation at Ser262 site by PAR-1 knockdown or by mutating the Ser262 site to unphosphorylatable alanine suppressed the enhancement of tau-induced neurodegeneration caused by milton knockdown. Furthermore, knockdown of milton or Miro increased the levels of active PAR-1. PubMed:22952452

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bp(GO:"apoptotic process") negativeCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

These data suggest that tau hyperphosphorylation at Thr231, Ser262, and Ser396 by DAPK1 renders the cells more resistant to the kinase-induced apoptotic cell death, providing new insights into the tau-involved apoptotic abortion in the course of chronic neurodegeneration. PubMed:23948915

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m(MIRBASE:"rno-mir-195") negativeCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

Endogenous miR-195 was knocked down using over-expression of its antisense molecule (pre-AMO-miR-195) via a lentivirus (lenti-pre-AMO-miR-195); this knockdown increased the tau phosphorylation at Ser202/Thr205, Ser262, Thr231, Ser422, and the Cdk5/p25 activation, but over-expression of miR-195 using lenti-pre-miR-195 decreased the tau phosphorylation and Cdk5/p25 activation. PubMed:26118667

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p(HGNC:MAPT, pmod(Ac, Lys, 280)) increases p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

hTau-K280Q mutants showed significantly increased phosphorylation on S262 as compared to both hTau-wt and hTau-K280R flies, when normalised to total hTau (K9JA) levels (**p < 0.01, one-way ANOVA, Fig. 4b,c). Mis-expression of pseudo-acetylated K280Q-hTau in the adult fly nervous system potently exacerbated fly locomotion defects and photoreceptor neurodegeneration. PubMed:26940749

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p(FPLX:"CAMK2_complex") increases p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

Several kinases such as microtubule-affinity regulating kinase (MARK), protein kinase A, calcium calmodulin kinase II, and checkpoint kinase 2 are known to phosphorylate tau on Ser(262) in vitro. In this study, we took advantage of the in situ proximity ligation assay to investigate the role of MARK2, one of the four MARK isoforms, in AD. We demonstrate that MARK2 interacts with tau and phosphorylates tau at Ser(262) in stably transfected NIH/3T3 cells expressing human recombinant tau. Staurosporine, a protein kinase inhibitor, significantly reduced the interaction between MARK2 and tau, and also phosphorylation of tau at Ser(262). PubMed:23001711

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act(p(FPLX:PKA), ma(kin)) directlyIncreases p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

Several kinases such as microtubule-affinity regulating kinase (MARK), protein kinase A, calcium calmodulin kinase II, and checkpoint kinase 2 are known to phosphorylate tau on Ser(262) in vitro. In this study, we took advantage of the in situ proximity ligation assay to investigate the role of MARK2, one of the four MARK isoforms, in AD. We demonstrate that MARK2 interacts with tau and phosphorylates tau at Ser(262) in stably transfected NIH/3T3 cells expressing human recombinant tau. Staurosporine, a protein kinase inhibitor, significantly reduced the interaction between MARK2 and tau, and also phosphorylation of tau at Ser(262). PubMed:23001711

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p(HBP:"PrP106-126") decreases p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

These finding highlight that treatment of PrP106-126 in cultured cells does not alter the level of total tau, but induces a reduction of p-tau262. PubMed:22692785

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p(HBP:"Tau antibody, AGG5759") increases p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

In parallel, phosphorylation of tau at Ser262 in MARK-transfected cells was investigated using a rabbit antibody recognizing phosphorylated Ser262 of tau (AGG5759) and a mouse anti-tau antibody (SC-21796) (Fig. S1a3). Tau was shown to interact with each of the transfected MARK isoforms (Fig. 1) and to be phosphorylated at Ser262 (Fig. 2). Staurosporine, a non-selective kinase inhibitor, significantly inhibited interactions between tau and each of the four MARK isoforms after treatment with 20 lM staurosporine for 1 h (Fig. 1; p = 0.02 for MARK1–, MARK2– and MARK3–tau interactions and p = 3 9 10-6 for MARK4–tau interaction). Treatment with staurosporine also significantly reduced PLA signals for tau phosphorylation at Ser262 (Fig. 2; p = 0.04 for MARK1- and p = 0.02 for MARK2- and MARK3- and p = 1 9 10-5 for MARK4-mediated tau phosphorylation) PubMed:23666762

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p(HBP:"Tau antibody, Tau-13") increases p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

In parallel, phosphorylation of tau at Ser262 in MARK-transfected cells was investigated using a rabbit antibody recognizing phosphorylated Ser262 of tau (AGG5759) and a mouse anti-tau antibody (SC-21796) (Fig. S1a3). Tau was shown to interact with each of the transfected MARK isoforms (Fig. 1) and to be phosphorylated at Ser262 (Fig. 2). Staurosporine, a non-selective kinase inhibitor, significantly inhibited interactions between tau and each of the four MARK isoforms after treatment with 20 lM staurosporine for 1 h (Fig. 1; p = 0.02 for MARK1–, MARK2– and MARK3–tau interactions and p = 3 9 10-6 for MARK4–tau interaction). Treatment with staurosporine also significantly reduced PLA signals for tau phosphorylation at Ser262 (Fig. 2; p = 0.04 for MARK1- and p = 0.02 for MARK2- and MARK3- and p = 1 9 10-5 for MARK4-mediated tau phosphorylation) PubMed:23666762

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p(HGNC:CHEK2) increases p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

Several kinases such as microtubule-affinity regulating kinase (MARK), protein kinase A, calcium calmodulin kinase II, and checkpoint kinase 2 are known to phosphorylate tau on Ser(262) in vitro. In this study, we took advantage of the in situ proximity ligation assay to investigate the role of MARK2, one of the four MARK isoforms, in AD. We demonstrate that MARK2 interacts with tau and phosphorylates tau at Ser(262) in stably transfected NIH/3T3 cells expressing human recombinant tau. Staurosporine, a protein kinase inhibitor, significantly reduced the interaction between MARK2 and tau, and also phosphorylation of tau at Ser(262). PubMed:23001711

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p(HGNC:DAPK1) increases p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

As shown in Figure 7a, compared with the vector control, DAPK1, but not DAPK1K42A, increased the phosphorylation of exogenous tau protein in HeLa cells, as detected by Thr231-specific (AT180), Ser262-specific, and Ser396-specific (PHF-13) antibodies that recognize specific tau phosphoepitopes and/or abnormal conformations specific to AD NFT. PubMed:24853415

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p(HGNC:DAPK1) increases p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

These data suggest that tau hyperphosphorylation at Thr231, Ser262, and Ser396 by DAPK1 renders the cells more resistant to the kinase-induced apoptotic cell death, providing new insights into the tau-involved apoptotic abortion in the course of chronic neurodegeneration. PubMed:23948915

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p(HGNC:MAPT, pmod(HBP:"O-GlcNAcylation")) positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 262)) 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

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act(p(HGNC:MARK1)) increases p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

Furthermore, silencing of both MARK1 and MARK2 blocked DAPK-induced tau S262 phosphorylation (Figure 3e). More importantly, a decrease of pS262 tau, but not total tau, was observed in brain extracts derived from DAPK−/− mice, compared with that from DAPK+/+ mice (Figure 3f). These results strongly suggest a role of endogenous DAPK in stimulating the activity of endogenous MARK, which in turn phosphorylates tau in neurons. PubMed:21311567

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act(p(HGNC:MARK1), ma(kin)) directlyIncreases p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

Using transgenic Drosophila expressing human tau, we found that RNAi-mediated knockdown of milton or Miro, an adaptor protein essential for axonal transport of mitochondria, enhanced human tau-induced neurodegeneration. Tau phosphorylation at an AD-related site Ser262 increased with knockdown of milton or Miro; and partitioning defective-1 (PAR-1), the Drosophila homolog of mammalian microtubule affinity-regulating kinase, mediated this increase of tau phosphorylation. Tau phosphorylation at Ser262 has been reported to promote tau detachment from microtubules, and we found that the levels of microtubule-unbound free tau increased by milton knockdown. Blocking tau phosphorylation at Ser262 site by PAR-1 knockdown or by mutating the Ser262 site to unphosphorylatable alanine suppressed the enhancement of tau-induced neurodegeneration caused by milton knockdown. Furthermore, knockdown of milton or Miro increased the levels of active PAR-1. PubMed:22952452

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act(p(HGNC:MARK2)) increases p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

Furthermore, silencing of both MARK1 and MARK2 blocked DAPK-induced tau S262 phosphorylation (Figure 3e). More importantly, a decrease of pS262 tau, but not total tau, was observed in brain extracts derived from DAPK−/− mice, compared with that from DAPK+/+ mice (Figure 3f). These results strongly suggest a role of endogenous DAPK in stimulating the activity of endogenous MARK, which in turn phosphorylates tau in neurons. PubMed:21311567

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act(p(HGNC:MARK2), ma(kin)) directlyIncreases p(HGNC:MAPT, pmod(Ph, Ser, 262)) 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

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act(p(HGNC:MARK2), ma(kin)) directlyIncreases p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

Several kinases such as microtubule-affinity regulating kinase (MARK), protein kinase A, calcium calmodulin kinase II, and checkpoint kinase 2 are known to phosphorylate tau on Ser(262) in vitro. In this study, we took advantage of the in situ proximity ligation assay to investigate the role of MARK2, one of the four MARK isoforms, in AD. We demonstrate that MARK2 interacts with tau and phosphorylates tau at Ser(262) in stably transfected NIH/3T3 cells expressing human recombinant tau. Staurosporine, a protein kinase inhibitor, significantly reduced the interaction between MARK2 and tau, and also phosphorylation of tau at Ser(262). PubMed:23001711

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p(HGNC:MARK4, pmod(Ph)) positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

Immunohistochemical analyses using isoform-selective antibodies demonstrated that MARK4 in a phosphorylated form colocalizes with p-tau Ser262 in granulovacuolar degeneration bodies (GVDs) that progressively accumulate in AD. PubMed:11943212

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Annotations
Disease Ontology (DO)
Alzheimer's disease

p(HGNC:RHOT1) decreases p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

Using transgenic Drosophila expressing human tau, we found that RNAi-mediated knockdown of milton or Miro, an adaptor protein essential for axonal transport of mitochondria, enhanced human tau-induced neurodegeneration. Tau phosphorylation at an AD-related site Ser262 increased with knockdown of milton or Miro; and partitioning defective-1 (PAR-1), the Drosophila homolog of mammalian microtubule affinity-regulating kinase, mediated this increase of tau phosphorylation. Tau phosphorylation at Ser262 has been reported to promote tau detachment from microtubules, and we found that the levels of microtubule-unbound free tau increased by milton knockdown. Blocking tau phosphorylation at Ser262 site by PAR-1 knockdown or by mutating the Ser262 site to unphosphorylatable alanine suppressed the enhancement of tau-induced neurodegeneration caused by milton knockdown. Furthermore, knockdown of milton or Miro increased the levels of active PAR-1. PubMed:22952452

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p(HGNC:TRAK1) decreases p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

Using transgenic Drosophila expressing human tau, we found that RNAi-mediated knockdown of milton or Miro, an adaptor protein essential for axonal transport of mitochondria, enhanced human tau-induced neurodegeneration. Tau phosphorylation at an AD-related site Ser262 increased with knockdown of milton or Miro; and partitioning defective-1 (PAR-1), the Drosophila homolog of mammalian microtubule affinity-regulating kinase, mediated this increase of tau phosphorylation. Tau phosphorylation at Ser262 has been reported to promote tau detachment from microtubules, and we found that the levels of microtubule-unbound free tau increased by milton knockdown. Blocking tau phosphorylation at Ser262 site by PAR-1 knockdown or by mutating the Ser262 site to unphosphorylatable alanine suppressed the enhancement of tau-induced neurodegeneration caused by milton knockdown. Furthermore, knockdown of milton or Miro increased the levels of active PAR-1. PubMed:22952452

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act(p(INTERPRO:"Kinase associated domain 1 (KA1)"), ma(kin)) positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 262)) 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

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a(CHEBI:"okadaic acid") increases p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

Similar findings have been observed in metabolically active rat brain slices, where a selective inhibition of PP2A with OA results in an aberrant phosphorylation of tau at the same residues seen in AD brains at serines (Ser) 198, 199, 202, 396, 404, 422 and 262 [11, 47, 48]. PubMed:22299660

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

Similar findings have been observed in metabolically active rat brain slices, where a selective inhibition of PP2A with OA results in an aberrant phosphorylation of tau at the same residues seen in AD brains at serines (Ser) 198, 199, 202, 396, 404, 422 and 262 [11, 47, 48]. PubMed:22299660

p(HGNC:PRKAA1) directlyIncreases p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

A recent study has demonstrated that activation of AMPKα1 enhances tau phosphorylation, while inhibition reduces tau phosphorylation at Ser-262, an epitope that is increased in early stages of AD, which promotes the autophagic degradation of tau [87] PubMed:29758300

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

A recent study has demonstrated that activation of AMPKα1 enhances tau phosphorylation, while inhibition reduces tau phosphorylation at Ser-262, an epitope that is increased in early stages of AD, which promotes the autophagic degradation of tau [87] PubMed:29758300

a(CHEBI:epoxomicin) positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 262)) 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

a(CHEBI:wortmannin) positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 262)) 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

a(HBP:"amyloid-beta oligomers") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 262)) 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

bp(GO:autophagy) increases deg(p(HGNC:MAPT, pmod(Ph, Ser, 262))) 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

act(p(FPLX:Proteasome)) increases deg(p(HGNC:MAPT, pmod(Ph, Ser, 262))) 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

p(HGNC:MARK1) directlyIncreases p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

For example,the phosphorylation of KXGS motifs (particularly Ser262) in the repeat domain of tau by MARK, PKA or CaMKII can reduce the affinity of tau to microtubules PubMed:26631930

p(HBP:"Tau oligomers", var("p.Lys280del")) causesNoChange p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

We did not observe any increase in the phosphorylation of the tau repeat domain (as seen by the antibody 12E8) after treating the neurons with TauRDΔK oligomers. PubMed:28528849

composite(p(HBP:"4R tau", var("p.Lys280del")), p(HGNC:STUB1)) negativeCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

Probing for phospho-tau with the 12E8 antibody in cell lysates from K18ΔK280 transfected cells reveals that tau phosphorylation is also decreased by CHIP overexpression (Fig. 1). PubMed:25374103

p(FPLX:PKA) directlyIncreases p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

For example,the phosphorylation of KXGS motifs (particularly Ser262) in the repeat domain of tau by MARK, PKA or CaMKII can reduce the affinity of tau to microtubules PubMed:26631930

p(HGNC:CAMK2A) directlyIncreases p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

For example,the phosphorylation of KXGS motifs (particularly Ser262) in the repeat domain of tau by MARK, PKA or CaMKII can reduce the affinity of tau to microtubules PubMed:26631930

Out-Edges 25

p(HGNC:MAPT, pmod(Ph, Ser, 262)) 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

p(HGNC:MAPT, pmod(Ph, Ser, 262)) 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

p(HGNC:MAPT, pmod(Ph, Ser, 262)) decreases bp(GO:"actin filament bundle assembly") View Subject | View Object

In addition, attachment of a phosphate group to S262 in the peptide Tau (254–284) decreased the affinity of the peptide for F-actin (Supplementary Fig. 1) and lowered the amount of Tau (254–284)-promoted actin bundles (Fig. 4f) PubMed:29215007

p(HGNC:MAPT, pmod(Ph, Ser, 262)) decreases complex(a(GO:"filamentous actin"), p(HGNC:MAPT, frag("254_284"))) View Subject | View Object

In addition, attachment of a phosphate group to S262 in the peptide Tau (254–284) decreased the affinity of the peptide for F-actin (Supplementary Fig. 1) and lowered the amount of Tau (254–284)-promoted actin bundles (Fig. 4f) PubMed:29215007

p(HGNC:MAPT, pmod(Ph, Ser, 262)) 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

p(HGNC:MAPT, pmod(Ph, Ser, 262)) 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

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Annotations
Uberon
brain

p(HGNC:MAPT, pmod(Ph, Ser, 262)) 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

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Annotations
Uberon
brain

p(HGNC:MAPT, pmod(Ph, Ser, 262)) 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

p(HGNC:MAPT, pmod(Ph, Ser, 262)) positiveCorrelation p(HGNC:MARK4, pmod(Ph)) View Subject | View Object

Immunohistochemical analyses using isoform-selective antibodies demonstrated that MARK4 in a phosphorylated form colocalizes with p-tau Ser262 in granulovacuolar degeneration bodies (GVDs) that progressively accumulate in AD. PubMed:11943212

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease

p(HGNC:MAPT, pmod(Ph, Ser, 262)) positiveCorrelation a(HBP:"granulovacuolar degeneration") View Subject | View Object

Immunohistochemical analyses using isoform-selective antibodies demonstrated that MARK4 in a phosphorylated form colocalizes with p-tau Ser262 in granulovacuolar degeneration bodies (GVDs) that progressively accumulate in AD. PubMed:11943212

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease

p(HGNC:MAPT, pmod(Ph, Ser, 262)) 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

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p(HGNC:MAPT, pmod(Ph, Ser, 262)) negativeCorrelation bp(GO:"apoptotic process") View Subject | View Object

These data suggest that tau hyperphosphorylation at Thr231, Ser262, and Ser396 by DAPK1 renders the cells more resistant to the kinase-induced apoptotic cell death, providing new insights into the tau-involved apoptotic abortion in the course of chronic neurodegeneration. PubMed:23948915

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p(HGNC:MAPT, pmod(Ph, Ser, 262)) negativeCorrelation m(MIRBASE:"rno-mir-195") View Subject | View Object

Endogenous miR-195 was knocked down using over-expression of its antisense molecule (pre-AMO-miR-195) via a lentivirus (lenti-pre-AMO-miR-195); this knockdown increased the tau phosphorylation at Ser202/Thr205, Ser262, Thr231, Ser422, and the Cdk5/p25 activation, but over-expression of miR-195 using lenti-pre-miR-195 decreased the tau phosphorylation and Cdk5/p25 activation. PubMed:26118667

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p(HGNC:MAPT, pmod(Ph, Ser, 262)) 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, 262)) positiveCorrelation a(HBP:Neurodegeneration) View Subject | View Object

Using transgenic Drosophila expressing human tau, we found that RNAi-mediated knockdown of milton or Miro, an adaptor protein essential for axonal transport of mitochondria, enhanced human tau-induced neurodegeneration. Tau phosphorylation at an AD-related site Ser262 increased with knockdown of milton or Miro; and partitioning defective-1 (PAR-1), the Drosophila homolog of mammalian microtubule affinity-regulating kinase, mediated this increase of tau phosphorylation. Tau phosphorylation at Ser262 has been reported to promote tau detachment from microtubules, and we found that the levels of microtubule-unbound free tau increased by milton knockdown. Blocking tau phosphorylation at Ser262 site by PAR-1 knockdown or by mutating the Ser262 site to unphosphorylatable alanine suppressed the enhancement of tau-induced neurodegeneration caused by milton knockdown. Furthermore, knockdown of milton or Miro increased the levels of active PAR-1. PubMed:22952452

Appears in Networks:

p(HGNC:MAPT, pmod(Ph, Ser, 262)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Similar findings have been observed in metabolically active rat brain slices, where a selective inhibition of PP2A with OA results in an aberrant phosphorylation of tau at the same residues seen in AD brains at serines (Ser) 198, 199, 202, 396, 404, 422 and 262 [11, 47, 48]. PubMed:22299660

p(HGNC:MAPT, pmod(Ph, Ser, 262)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

A recent study has demonstrated that activation of AMPKα1 enhances tau phosphorylation, while inhibition reduces tau phosphorylation at Ser-262, an epitope that is increased in early stages of AD, which promotes the autophagic degradation of tau [87] PubMed:29758300

p(HGNC:MAPT, pmod(Ph, Ser, 262)) increases bp(GO:autophagy) View Subject | View Object

A recent study has demonstrated that activation of AMPKα1 enhances tau phosphorylation, while inhibition reduces tau phosphorylation at Ser-262, an epitope that is increased in early stages of AD, which promotes the autophagic degradation of tau [87] PubMed:29758300

p(HGNC:MAPT, pmod(Ph, Ser, 262)) 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

p(HGNC:MAPT, pmod(Ph, Ser, 262)) 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

p(HGNC:MAPT, pmod(Ph, Ser, 262)) 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

p(HGNC:MAPT, pmod(Ph, Ser, 262)) negativeCorrelation composite(p(HBP:"4R tau", var("p.Lys280del")), p(HGNC:STUB1)) View Subject | View Object

Probing for phospho-tau with the 12E8 antibody in cell lysates from K18ΔK280 transfected cells reveals that tau phosphorylation is also decreased by CHIP overexpression (Fig. 1). PubMed:25374103

p(HGNC:MAPT, pmod(Ph, Ser, 262)) decreases complex(a(GO:microtubule), p(HGNC:MAPT)) View Subject | View Object

For example,the phosphorylation of KXGS motifs (particularly Ser262) in the repeat domain of tau by MARK, PKA or CaMKII can reduce the affinity of tau to microtubules PubMed:26631930

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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.