Disease relevance of DYRK1A

• In human, DYRK1A encodes a serine-threonine kinase but despite its potential involvement in the neurobiological alterations associated with Down syndrome, its physiological function has not yet been defined [1].
• In neuroblastoma cells, Abeta induced an increase in the DYRK1A transcript, which also led to tau phosphorylation at Thr(212) under the overexpression of tau [2].
• Consistent with our model, substitution of Tyr-321 but not of Tyr-319 by phenylalanine markedly reduced the enzymic activity of recombinant DYRK1A expressed in either Escherichia coli or mammalian cells [3].

Psychiatry related information on DYRK1A

• The DYRK1A gene on human chromosome 21 encodes a protein kinase presumed to be involved in the pathogenesis of mental retardation in Down's syndrome [4].
• These mice represent the most clinically relevant DYRK1A mouse model to date and provide us a valuable tool for the in vivo study of mechanisms that underlie the learning and memory deficit in DS [5].
• The DYRK isoforms also phosphorylate human microtubule-associated protein tau at Thr(212) in vitro, a residue that is phosphorylated in foetal tau and hyperphosphorylated in filamentous tau from Alzheimer's-disease brain [6].

High impact information on DYRK1A

• This complex also serves as a transcriptional repressor of DYRK1A, a candidate gene for Down's syndrome [7].
• Furthermore, compared with that in normal fetal brain, the expression of AP4 and geminin is reduced in Down's syndrome fetal brain at 20 weeks of gestation age, at which time premature overexpression of dual-specificity tyrosine-phosphorylated and regulated kinase 1A (DYRK1A) is observed [7].
• The DYRK1A gene, encoded in chromosome 21 Down syndrome critical region, bridges between {beta}-amyloid production and tau phosphorylation in Alzheimer disease [2].
• Our result indicates that DYRK1A could be a key molecule bridging between beta-amyloid production and tau phosphorylation in AD [2].
• In logistic regression, the DYRK1A (dual-specificity tyrosine-regulated kinase 1A) gene, located in the Down syndrome critical region, showed the highest significance [OR = 2.99 (95% CI: 1.72-5.19), P = 0.001], whereas the RUNX1 gene showed a high odds ratio [OR = 23.3 (95% CI: 2.76-196.5), P = 0.038] [2].

Chemical compound and disease context of DYRK1A

• Despite its potential involvement in the neurobiological alterations observed in Down syndrome patients, the biological functions of the serine/threonine kinase DYRK1A have not been identified yet [8].
• DYRK1A, dual-specificity tyrosine-regulated kinase 1A, maps to human chromosome 21 within the Down syndrome (DS) critical region [9].
• As Dyrk1A is an activator of steroid hormone-regulated transcription, the overexpression of DYRK1A in persons with Down syndrome may cause rather broad changes in the homeostasis of steroid hormone-controlled cellular events [10].
• MNB/DYRK1A is a proline-directed serine/threonine kinase implicated in Down syndrome (DS) [11].
• Minibrain kinase/dual-specificity tyrosine phosphorylation regulated kinase 1A (MNB/DYRK1A) is a proline/arginine-directed serine/threonine kinase implicated in the learning deficits of Down syndrome [12].

Biological context of DYRK1A

• In order to define the consensus sequence for the substrate specificity of DYRK1A, a library of 300 peptides was designed in variation of the H3 phosphorylation site [13].
• This marked difference in substrate specificity between DYRK1A and ERK2 can be explained by the requirement for an arginine at the P -3 site of DYRK substrates and its presumed interaction with aspartate 247 conserved in all DYRKs [13].
• Thus DYRK1A protein kinase may play a role in regulating the biogenesis of the splicing speckle compartment [14].
• Furthermore, immunofluorescence analysis of PC12 cells co-transfected with both plasmids showed a re-distribution of DYRK1A from the nucleus to the cytoplasm where it co-localized with PAHX-AP1 [1].
• The amino acid sequences of DYRK1A and DYRK1B are 84% identical in the N-terminus and the catalytic domain but show no extended sequence similarity in the C-terminal region [4].

Anatomical context of DYRK1A

• Co-expression of DYRK1A, DYRK1B, or DYRK2 with a series of glycogen synthase mutants with Ser/Ala substitutions at the phosphorylation sites in COS cells revealed that protein kinases cause phosphorylation of site 3a in glycogen synthase [15].
• DYRK1A exhibited a punctate pattern of GFP fluorescence inside the nucleus and was co-purified with the nuclear matrix [16].
• This interaction was confirmed by co-immunoprecipitation of PC12 cells co-transfected with DYRK1A and PAHX-AP1 [1].
• Here we describe a highly similar homolog, DYRK1B, which is, in contrast to DYRK1A, predominately expressed in muscle and testis [4].
• We have also purified a protein kinase to near homogeneity from rabbit skeletal muscle that phosphorylates FKHR at Ser(329) specifically and identified it as DYRK1A (dual-specificity tyrosine-phosphorylated and regulated kinase 1A) [17].

Associations of DYRK1A with chemical compounds

• Characterization of cyclin L2, a novel cyclin with an arginine/serine-rich domain: phosphorylation by DYRK1A and colocalization with splicing factors [18].
• Another polypeptide was identified as DYRK1A, a member of the dual-specificity tyrosine phosphorylated and regulated protein kinase (DYRK) family [15].
• Evaluation of the phosphate incorporation into these peptides identified DYRK1A as a proline-directed kinase with a phosphorylation consensus sequence (RPX(S/T)P) similar to that of ERK2 (PX(S/T)P) [13].
• We identified a single phosphorylated amino acid residue in the DYRK substrate histone H3 (threonine 45) by mass spectrometry, phosphoamino acid analysis, and protein sequencing [13].
• A catalytically inactive mutant of DYRK1A contained no detectable phosphotyrosine, indicating that Tyr-321 is autophosphorylated by DYRK1A [3].

Enzymatic interactions of DYRK1A

• These experiments suggest that DYRK1A may phosphorylate FKHR at Ser(329) in vivo [17].
• Here we describe the identification of DYRK1A as a protein kinase that phosphorylates SF3b1 in vitro and in cultivated cells [19].
• In addition, Dyrk1 directly phosphorylates CREB, leading to the stimulation of subsequent CRE-mediated gene transcription during the neuronal differentiation in H19-7 cells [20].

Regulatory relationships of DYRK1A

• These data characterize cyclin L2 as a highly mobile component of nuclear speckles and suggest that DYRK1A may regulate splicing by phosphorylation of cyclin L2 [18].
• GLI1-dependent transcription is positively regulated by DYRK1A, which is reported to bind HAN11 [21].
• HAN11 and mDia1 repressed DYRK1A-dependent GLI1 transcriptional activity [21].
• Protein kinase Dyrk1 activates cAMP response element-binding protein during neuronal differentiation in hippocampal progenitor cells [20].

Other interactions of DYRK1A

• By fluorescence microscopy and subcellular fractionation, a green fluorescent protein (GFP) fusion protein of DYRK1A was found to accumulate in the nucleus of transfected COS-7 and HEK293 cells, whereas GFP-DYRK2 was predominantly detected in the cytoplasm [16].
• Dual-specificity tyrosine-phosphorylated and regulated kinase 1A (DYRK1A) interacts with the phytanoyl-CoA alpha-hydroxylase associated protein 1 (PAHX-AP1), a brain specific protein [1].
• A peptide designed after the optimal substrate sequence (DYRKtide) was efficiently phosphorylated by DYRK1A (K(m) = 35 microM) but not by ERK2 [13].
• RESULTS: Overexpression of DYRK1A caused a markedly increased phosphorylation of SF3b1 in COS-7 cells as assessed by Western blotting with an antibody specific for phosphorylated Thr-Pro dipeptide motifs [19].
• The protein kinase DYRK1A phosphorylates the splicing factor SF3b1/SAP155 at Thr434, a novel in vivo phosphorylation site [19].

Analytical, diagnostic and therapeutic context of DYRK1A

• The information provided here should be valuable for MNBH mutation studies and aid in the development of DS animal models [22].
• Fluorescence in situ hybridization and regional mapping data localize DYRK between markers D21S336 and D21S337 in the 21q22.2 region [23].
• Northern blot analysis indicated that almost all the MNB/DYRK transcripts start from the newly identified 5'-noncoding exon [24].
• PCR amplification of cDNAs from various human tissues indicated that some mRNAs contain an additional noncoding exon of 76 bp next to the 5'-end exon and there are at least three types of MNB/DYRK mRNAs containing alternatively spliced 5' exons including two novel exons [24].
• This report describes the mapping of MNBH to a single locus on human chromosome 21q22.2 by FISH and Southern blotting [25].

References