Activation, regulation, and inhibition of DYRK1A

Becker, Walter; Sippl, Wolfgang

doi:10.1111/j.1742-4658.2010.07956.x

Cited by 186 publications

(175 citation statements)

References 87 publications

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“…In contrast to MAPK, the critical tyrosines in DYRK and GSK3 appear to be constitutively phosphorylated and serve no regulatory function [13]. Collectively, these findings support the hypothesis that this mechanism of autoactivation also applies to other CMGC kinases that are not regulated by upstream kinases [15,16]. However, it must be noted that even the role of tyrosine phosphorylation in the activation of DYRK1A is not uncontested [17].…”

Section: Introductionmentioning

confidence: 56%

“…Phosphorylation of this tyrosine stabilizes the active conformation by allowing electrostatic interactions of the phosphate with two conserved arginine residues [7]. Only the members of the MAPK family are regulated by upstream kinases (MAP2K), whereas DYRKs, homeodomain-interacting protein kinase 2 (HIPK2), GSK3 and intestinal cell kinase autophosphorylate on the corresponding tyrosine [8][9][10][11]. On the other hand, CLKs lack the conserved tyrosine residue in the activation loop but are also capable of tyrosine autophosphorylation [4,6,12].…”

Section: Introductionmentioning

confidence: 99%

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Mechanism of dual specificity kinase activity of DYRK1A

et al. 2013

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The function of many protein kinases is controlled by the phosphorylation of a critical tyrosine residue in the activation loop. Dual specificity tyrosinephosphorylation-regulated kinases (DYRKs) autophosphorylate on this tyrosine residue but phosphorylate substrates on aliphatic amino acids. This study addresses the mechanism of dual specificity kinase activity in DYRK1A and related kinases. Tyrosine autophosphorylation of DYRK1A occurred rapidly during in vitro translation and did not depend on the non-catalytic domains or other proteins. Expression in bacteria as well as in mammalian cells revealed that tyrosine kinase activity of DYRK1A is not restricted to the co-translational autophosphorylation in the activation loop. Moreover, mature DYRK1A was still capable of tyrosine autophosphorylation. Point mutants of DYRK1A and DYRK2 lacking the activation loop tyrosine showed enhanced tyrosine kinase activity. A series of structurally diverse DYRK1A inhibitors was used to pharmacologically distinguish different conformational states of the catalytic domain that are hypothesized to account for the dual specificity kinase activity. All tested compounds inhibited substrate phosphorylation with higher potency than autophosphorylation but none of the tested inhibitors differentially inhibited threonine and tyrosine kinase activity. Finally, the related cyclin-dependent kinase-like kinases (CLKs), which lack the activation loop tyrosine, autophosphorylated on tyrosine both in vitro and in living cells. We propose a model of DYRK autoactivation in which tyrosine autophosphorylation in the activation loop stabilizes a conformation of the catalytic domain with enhanced serine/threonine kinase activity without disabling tyrosine phosphorylation. The mechanism of dual specificity kinase activity probably applies to related serine/threonine kinases that depend on tyrosine autophosphorylation for maturation. Structured digital abstract• CLK1 and CLK1 phosphorylate by protein kinase assay (View interaction)• HIPK2 and HIPK2 phosphorylate by protein kinase assay (View interaction)• DYRK1A phosphorylates SF3B1 by protein kinase assay (View interaction)• DYRK1A and DYRK1A phosphorylate by protein kinase assay (View interaction)

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Section: Introductionmentioning

confidence: 56%

Section: Introductionmentioning

confidence: 99%

Mechanism of dual specificity kinase activity of DYRK1A

et al. 2013

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“…DYRK1As' catalytic activity is not modulated by phosphorylation, in contrast to most kinases whose activity is turned on or off by kinase or phosphatase. 6 However, to achieve full kinase activity, one fully conserved tyrosine (Tyr 321) in the activation loop must be constitutively autophosphorylated immediately after translation. 25 E2F1, FOXO1, GLI1, GSK3, INI1/SNF5, NFAT, RAS, RAF, MEK1, SRSF6, STAT3, SJI1, and SIRT1.…”

Section: Discussionmentioning

confidence: 99%

“…3 The extra copy of DYRK1A in individuals with Down syndrome (DS) accounts for the majority of their phenotypic features, 4 and DYRK1A overexpression may be the underlying mechanism for abnormal brain development in DS individuals. 5,6 Furthermore, data from both animal models and humans have suggested that decreased DYRK1A expression is also pathogenic. [7][8][9] Pathogenic variants in DYRK1A resulting in haploinsufficiency of the gene have recently been proposed to cause intellectual disability (ID), mental retardation autosomal dominant type 7 (MIM 614104) in individuals with translocations, 10 single-nucleotide variants (SNVs), 11,12 and intragenic microdeletions 11,[13][14][15][16][17] disrupting only DYRK1A.…”

Section: Introductionmentioning

confidence: 99%

DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies

et al. 2015

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Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A ) is a highly conserved gene located in the Down syndrome critical region. It has an important role in early development and regulation of neuronal proliferation. Microdeletions of chromosome 21q22.12q22.3 that include DYRK1A (21q22.13) are rare and only a few pathogenic single-nucleotide variants (SNVs) in the DYRK1A gene have been described, so as of yet, the landscape of DYRK1A disruptions and their associated phenotype has not been fully explored. We have identified 14 individuals with de novo heterozygous variants of DYRK1A; five with microdeletions, three with small insertions or deletions (INDELs) and six with deleterious SNVs. The analysis of our cohort and comparison with published cases reveals that phenotypes are consistent among individuals with the 21q22.12q22.3 microdeletion and those with translocation, SNVs, or INDELs within DYRK1A. All individuals shared congenital microcephaly at birth, intellectual disability, developmental delay, severe speech impairment, short stature, and distinct facial features. The severity of the microcephaly varied from − 2 SD to − 5 SD. Seizures, structural brain abnormalities, eye defects, ataxia/broadbased gait, intrauterine growth restriction, minor skeletal abnormalities, and feeding difficulties were present in two-thirds of all affected individuals. Our study demonstrates that haploinsufficiency of DYRK1A results in a new recognizable syndrome, which should be considered in individuals with Angelman syndrome-like features and distinct facial features. Our report represents the largest cohort of individuals with DYRK1A disruptions to date, and is the first attempt to define consistent genotype-phenotype correlations among subjects with 21q22.13 microdeletions and DYRK1A SNVs or small INDELs.

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“…This gene encodes a protein kinase that performs crucial functions in the regulation of cell proliferation and multiple signaling pathways (Guedj et al, 2012;Becker and Sippl, 2011) that contribute to normal brain development and adult brain physiology (Becker and Sippl, 2011;Tejedor and Hämmerle, 2011).…”

Section: Introductionmentioning

confidence: 99%

Normalizing the gene dosage of Dyrk1A in a mouse model of Down syndrome rescues several Alzheimer's disease phenotypes

García-Cerro

Rueda

Vidal

et al. 2017

Neurobiology of Disease

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The intellectual disability that characterizes Down syndrome (DS) is primarily caused by prenatal changes in central nervous system growth and differentiation. However, in later life stages, the cognitive abilities of DS individuals progressively decline due to accelerated aging and the development of Alzheimer's disease (AD) neuropathology. The AD neuropathology in DS has been related to the overexpression of several genes encoded by Hsa21 including DYRK1A (dualspecificity tyrosine-(Y)-phosphorylation regulated kinase 1A), which encodes a protein kinase that performs crucial functions in the regulation of multiple signaling pathways that contribute to normal brain development and adult brain physiology. Studies performed in vitro and in vivo in animal models overexpressing this gene have demonstrated that the DYRK1A gene also plays a crucial role in several neurodegenerative processes found in DS. The Ts65Dn (TS) mouse bears a partial triplication of several Hsa21 orthologous genes, including Dyrk1A, and replicates many DS-like abnormalities, including age-dependent cognitive decline, cholinergic neuron degeneration, increased levels of APP and Aβ, and tau hyperphosphorylation. To use a more direct approach to evaluate the role of the gene dosage of Dyrk1A on the neurodegenerative profile of this model, TS mice were crossed with Dyrk1A KO mice to obtain mice with a triplication of a segment of Mmu16 that includes this gene, mice that are trisomic for the same genes but only carry two copies of Dyrk1A, euploid mice with a normal Dyrk1A dosage, and CO animals with a single copy of Dyrk1A. Normalizing the gene dosage of Dyrk1A in the TS mouse rescued the density of senescent cells in the cingulate cortex, hippocampus and septum, prevented cholinergic neuron degeneration, and reduced App expression in the hippocampus, Aβ load in the cortex and hippocampus, the expression of phosphorylated tau at the Ser202 residue in the hippocampus and cerebellum and the levels of total tau in the cortex, hippocampus and cerebellum. Thus, the present study provides further support for the role of the Dyrk1A gene in several AD-like phenotypes found in TS mice and indicates that this gene could be a therapeutic target to treat AD in DS.

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Activation, regulation, and inhibition of DYRK1A

Cited by 186 publications

References 87 publications

Mechanism of dual specificity kinase activity of DYRK1A

Mechanism of dual specificity kinase activity of DYRK1A

DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies

Normalizing the gene dosage of Dyrk1A in a mouse model of Down syndrome rescues several Alzheimer's disease phenotypes

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