p(HGNC:MARK1)

Entity

Name

MARK1

Namespace

hgnc

Namespace Version

20180906

Namespace URL

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

Tau Modifications Sections of NESTOR

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

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

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

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

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

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

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

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

Other serine and threonine residues, not followed by proline, are phosphorylated by other protein kinases, including microtubule-affinity-regulating kinase (MARK) (Drewes et al., 1993), calcium/ calmodulin kinase II (CAMKII), cAMP-dependent kinase (PKA) (Johnson et al., 1992), and casein kinase II (Greenwood et al., 1994). PubMed:12428809

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

Other phosphorylation sites in or near the repeat domain are phosphorylated by microtubule affinity-regulating kinases (MARKs; also known as PAR1 kinases), cyclic AMP-dependent protein kinase (PKA) and Ca2+- or calmodulin-dependent protein kinase II (CaMKII), among others PubMed:26631930