Form of dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1A nonphosphorylated at tyrosine 145 and 147 is enriched in the nuclei of astroglial cells, adult hippocampal progenitors, and some cholinergic axon terminals

Kida, E; Walus, Marius; Jarząbek, Katarzyna; Palminiello, Sonia; Albertini, G.; Rabe, Ausma; Hwang, Yu Wen; Golabek, Adam A.

doi:10.1016/j.neuroscience.2011.08.028

Cited by 15 publications

(20 citation statements)

References 73 publications

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“…Consistent with the observation that Dyrk1A has a nuclear localization sequence [2], some Dyrk1A was observed in the nucleus. This kinase was also found in soma ( open arrows ) and dendrites ( arrows ), which is consistent with the earlier results using mouse monoclonal antibodies 7F3 [10] and 7D10 [26]. Clathrin was detected in the perinuclear area of the cell soma ( open arrow ) and in dendrites and axons (arrows in panels b,e ), but not in the nuclei.…”

Section: Resultssupporting

confidence: 91%

“…Adult female mice (B6EiC3) (Jackson Laboratory; Bar Harbor, ME) were perfused with 0.5% glutaraldehyde/2% formaldehyde in 0.1 M PBS, and various parts of the brain were dissected out as described before [26]. Immunofluorescence was performed on 40-µm free-floating Vibratome sections, according to the methods described earlier [26] but with modifications. In brief, each brain section was blocked for 4 hr at room temperature in 10% FCS/PBS with 0.1% saponin, then incubated for 24 hr at 4°C with primary antibodies diluted in 10%FCS/PBS/1% saponin.…”

Section: Methodsmentioning

confidence: 99%

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Phosphorylation by Dyrk1A of Clathrin Coated Vesicle-Associated Proteins: Identification of the Substrate Proteins and the Effects of Phosphorylation

et al. 2012

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Dyrk1A phosphorylated multiple proteins in the clathrin-coated vesicle (CCV) preparations obtained from rat brains. Mass spectrometric analysis identified MAP1A, MAP2, AP180, and α- and β-adaptins as the phosphorylated proteins in the CCVs. Each protein was subsequently confirmed by [32P]-labeling and immunological methods. The Dyrk1A-mediated phosphorylation released the majority of MAP1A and MAP2 and enhanced the release of AP180 and adaptin subunits from the CCVs. Furthermore, Dyrk1A displaced adaptor proteins physically from CCVs in a kinase-concentration dependent manner. The clathrin heavy chain release rate, in contrast, was not affected by Dyrk1A. Surprisingly, the Dyrk1A-mediated phosphorylation of α- and β-adaptins led to dissociation of the AP2 complex, and released only β-adaptin from the CCVs. AP180 was phosphorylated by Dyrk1A also in the membrane-free fractions, but α- and β-adaptins were not. Dyrk1A was detected in the isolated CCVs and was co-localized with clathrin in neurons from mouse brain sections and from primary cultured rat hippocampus. Previously, we proposed that Dyrk1A inhibits the onset of clathrin-mediated endocytosis in neurons by phosphorylating dynamin 1, amphiphysin 1, and synaptojanin 1. Current results suggest that besides the inhibition, Dyrk1A promotes the uncoating process of endocytosed CCVs.

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Section: Resultssupporting

confidence: 91%

Section: Methodsmentioning

confidence: 99%

Phosphorylation by Dyrk1A of Clathrin Coated Vesicle-Associated Proteins: Identification of the Substrate Proteins and the Effects of Phosphorylation

et al. 2012

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“…These residues are not present in the standard NAPA2 region of DYRK2, and DYRK2 does not have an equivalent interaction between the DH box and NAPA2 regions (Figure 3B). Recent evidence suggests phosphorylation of DYRK1A at Tyr145 and Tyr147 may have important regulatory roles (Kida et al., 2011). Tyr145 is solvent exposed, but phosphorylation of Tyr147 would change its interactions significantly, although it is not possible to predict whether this would be favorable or unfavorable, because pTyr147 could maintain interactions with Arg231 and replace the interactions of Glu153.…”

Section: Resultsmentioning

confidence: 99%

“…Although all the identified phosphorylation sites are conserved within the DYRK family and also across various species, the Tyr phosphorylation is weak, and any physiological significance of phosphorylation at these phosphorylation sites is yet to be established. Interestingly, phosphorylation on Tyr145 and Tyr147 has recently been identified as a modification that determines nuclear localization of DYRK1A in neurons (Kida et al., 2011). …”

Section: Resultsmentioning

confidence: 99%

Structures of Down Syndrome Kinases, DYRKs, Reveal Mechanisms of Kinase Activation and Substrate Recognition

et al. 2013

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SummaryDual-specificity tyrosine-(Y)-phosphorylation-regulated kinases (DYRKs) play key roles in brain development, regulation of splicing, and apoptosis, and are potential drug targets for neurodegenerative diseases and cancer. We present crystal structures of one representative member of each DYRK subfamily: DYRK1A with an ATP-mimetic inhibitor and consensus peptide, and DYRK2 including NAPA and DH (DYRK homology) box regions. The current activation model suggests that DYRKs are Ser/Thr kinases that only autophosphorylate the second tyrosine of the activation loop YxY motif during protein translation. The structures explain the roles of this tyrosine and of the DH box in DYRK activation and provide a structural model for DYRK substrate recognition. Phosphorylation of a library of naturally occurring peptides identified substrate motifs that lack proline in the P+1 position, suggesting that DYRK1A is not a strictly proline-directed kinase. Our data also show that DYRK1A wild-type and Y321F mutant retain tyrosine autophosphorylation activity.

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“…Anti-DYRK1A antibody 8D9 is an in-house produced monoclonal antibody raised against peptides containing the first 160 residues of rat DYRK1A (31), with the epitope located between residues 142–147 (isoform 1 numbering) containing non-phosphorylated Tyr-145 (32). Mouse monoclonal anti-DYRK1A antibody 7F3, with the epitope located between residues 74–78, was raised similarly as 8D9 (33).…”

Section: Methodsmentioning

confidence: 99%

Gene Dosage-Dependent Association of DYRK1A With the Cytoskeleton in the Brain and Lymphocytes of Down Syndrome Patients

Dowjat

Adayev

Kaczmarski

et al. 2012

J Neuropathol Exp Neurol

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The triplication of the DYRK1A gene encoding proline-directed serine/threonine kinase and located in the critical region of Down syndrome (DS) has been implicated in cognitive deficits and intellectual disability of individuals with DS. We investigated the effect of abnormal levels of this kinase on the cytoskeleton in brain and peripheral tissues of DS subjects. In DS tissues, the predictable ≈1.5-fold enhancement of the levels of DYRK1A protein was demonstrated. An association of DYRK1A with all 3 major cytoskeleton networks was identified using immunoprecipitation. We concentrated on the actin cytoskeleton because its association with DYRK1A was the most affected by the enzyme levels. As measured by co-immunoprecipitation in DS tissues, but not in fragile X lymphocytes, actin association with DYRK1A was reduced. This reduced association was dependent on the state of phosphorylation of cytoskeletal proteins and was present only in cells overproducing DYRK1A kinase; therefore, the effect was attributable to the DYRK1A gene dosage. Alterations of DYRK1A-actin assemblies were detected in newborn and infant groups, thereby linking DYRK1A overexpression with abnormal brain development of DS children. The identification of the actin cytoskeleton as one of cellular targets of DYRK1A action provides new insights into a gene-dosage-sensitive mechanism by which DYRK1A could contribute to the pathogenesis of DS. In addition, the presence of this DS-specific cytoskeleton anomaly in lymphocytes attests to the systemic nature of some features of DS. To our knowledge this is the first study conducted in human tissue that shows DYRK1A association with the cytoskeleton.

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Form of dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1A nonphosphorylated at tyrosine 145 and 147 is enriched in the nuclei of astroglial cells, adult hippocampal progenitors, and some cholinergic axon terminals

Cited by 15 publications

References 73 publications

Phosphorylation by Dyrk1A of Clathrin Coated Vesicle-Associated Proteins: Identification of the Substrate Proteins and the Effects of Phosphorylation

Phosphorylation by Dyrk1A of Clathrin Coated Vesicle-Associated Proteins: Identification of the Substrate Proteins and the Effects of Phosphorylation

Structures of Down Syndrome Kinases, DYRKs, Reveal Mechanisms of Kinase Activation and Substrate Recognition

Gene Dosage-Dependent Association of DYRK1A With the Cytoskeleton in the Brain and Lymphocytes of Down Syndrome Patients

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