p(HGNC:MARK2)

Entity

Name

MARK2

Namespace

hgnc

Namespace Version

20180906

Namespace URL

https://raw.githubusercontent.com/pharmacome/terminology/b46b65c3da259b6e86026514dfececab7c22a11b/external/hgnc-names.belns

Importantly, MARK2-based phosphorylation of tau is accelerated by the priming activity of either Cdk5 or GSK3b [29], suggesting that tau phosphorylation involves a series of ordered kinase events. PubMed:21882945

Importantly, MARK2-based phosphorylation of tau is accelerated by the priming activity of either Cdk5 or GSK3b [29], suggesting that tau phosphorylation involves a series of ordered kinase events. PubMed:21882945

Western blot analysis for a panel of tau kinases showed that only the levels of endogenous Cdk5 and Akt were significantly reduced by Cdc37 siRNA; the levels of GSK3-Beta and Mark2 (microtubule affinity regulating kinase 2) were largely unchanged PubMed:21367866

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

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

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

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

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

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

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

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

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

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

Phosphorylation of tau by the kinases GSK3b, Cdk5 and MARK2 is a major regulator of its microtubule interactions PubMed:21882945

Importantly, MARK2-based phosphorylation of tau is accelerated by the priming activity of either Cdk5 or GSK3b [29], suggesting that tau phosphorylation involves a series of ordered kinase events. PubMed:21882945

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

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

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

Importantly, depletion of MARK1/2 reversed the inhibitory effect of DAPK on MT regrowth (Figure 5c, right panel). These results indicate that the DAPK–MARK signaling axis inhibits MT assembly and stability. PubMed:21311567

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

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

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

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

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

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

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

In particular, previous studies have demonstrated that the tau ubiquitin ligase, CHIP, is unable to bind and ubiquitinate tau species phosphorylated by Par-1/MARK2 on the 12E8 epitope (S262/356) [33], a p-tau species that is also resistant to degradation upon treatment with Hsp90 inhibitors [32,33]. Tau phosphorylated at the PHF1 epitope (S396/404) is still susceptible to degradation following Hsp90 inhibition and actually exhibits an enhanced interaction with Hsp90 PubMed:25031639