Cloning of a Human Homolog of theDrosophila Minibrain/Rat Dyrk Gene from “the Down Syndrome Critical Region” of Chromosome 21

Shindoh, Nobuaki; Kudoh, Jun; Maeda, Hinako; Yamaki, Akiko; Minoshima, Shinsei; Shimizu, Yoshiko; Shimizu, Nobuyoshi

doi:10.1006/bbrc.1996.1135

Cited by 113 publications

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“…In situ hybridization studies show that DYRK1A is highly expressed in brain gray matter, spinal cord, and retina in developing murine embryos (Song et al, 1996;Rahmani et al, 1998;Hämmerle et al, 2003a;Mao et al, 2003;Marti et al, 2003) and in the cerebral cortex, cerebellum, and pyramidal cell layer in the hippocampus in adult mice (Guimera et al, 1996). DYRK1A has been considered a good candidate gene for the Down syndrome phenotypic abnormalities (reviewed in Epstein, 2000;Vicari et al, 2000;Nadel, 2003) due to its localization in the Down syndrome critical region of chromosome 21 (Rahmani et al, 1989(Rahmani et al, , 1990Delabar et al, 1993;Shindoh et al, 1996;Song et al, 1996), its overexpression in the brain of Down syndrome patients (Guimera et al, 1999), and the neurobehavioral alterations shown by transgenic mice overexpressing the gene (Smith and Rubin, 1997;Altafaj et al, 2001). The recent observation that the size of dendrites in some brain areas is reduced in DYRK1A haploinsufficient mice indicates that DYRK1A dose reduction could affect the length and the complexity of the dendrites (Fotaki et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…The human Dyrk1A gene maps to the 21q22.2 region of chromosome 21, in the Down syndrome critical region (Rahmani et al, 1989(Rahmani et al, , 1990Delabar et al, 1993;Shindoh et al, 1996;Song et al, 1996), and transgenic mice harboring an extra copy of this gene exhibit cognitive deficits and motor abnormalities characteristic of Down syndrome (Smith and Rubin, 1997;Altafaj et al, 2001). The human and rodent Dyrk1A gene are ubiquitously expressed in adult and fetal tissues with high expression in the brain and the heart during development (Guimera et al, 1996(Guimera et al, , 1999Song et al, 1996;Rahmani et al, 1998;Hämmerle et al, 2003a;Mao et al, 2003;Marti et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…This is caused by the abnormal spacing of neuroblasts and a reduction in the production of neuronal progeny (Tejedor et al, 1995). At least seven closely related homologous mammalian kinases in the DYRK family have since been isolated (Guimera et al, 1996(Guimera et al, , 1999Shindoh et al, 1996;Song et al, 1996Song et al, , 1997Raich et al, 2003). The DYRK family possesses serine and threonine phosphorylation activity as well as autophosphorylation activity on tyrosine residues (Kentrup et al, 1996;Becker et al, 1998;Becker and Joost, 1999;Himpel et al, 2000).…”

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DYRK1A Enhances the Mitogen-activated Protein Kinase Cascade in PC12 Cells by Forming a Complex with Ras, B-Raf, and MEK1

Kelly

Rahmani

2005

MBoC

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Dual-specificity tyrosine-phosphorylated and regulated kinase 1A (Dyrk1A) is the human homologue of the Drosophila mnb (minibrain) gene. In Drosophila, mnb is involved in postembryonic neurogenesis. In human, DYRK1A maps within the Down syndrome critical region of chromosome 21 and is overexpressed in Down syndrome embryonic brain. 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. Here, we report that DYRK1A overexpression potentiates nerve growth factor (NGF)-mediated PC12 neuronal differentiation by up-regulating the Ras/MAP kinase signaling pathway independently of its kinase activity. Furthermore, we show that DYRK1A prolongs the kinetics of ERK activation by interacting with Ras, B-Raf, and MEK1 to facilitate the formation of a Ras/B-Raf/MEK1 multiprotein complex. These data indicate that DYRK1A may play a critical role in Ras-dependent transducing signals that are required for promoting or maintaining neuronal differentiation and suggest that overexpression of DYRK1A may contribute to the neurological abnormalities observed in Down syndrome patients. INTRODUCTIONMinibrain (mnb)/dual-specificity tyrosine-phosphorylated and regulated kinase 1A (Dyrk1A) gene is a member of a growing family of protein kinases called DYRK. In Drosophila, mnb seems to play an essential role during postembryonic neurogenesis. Mutant flies are characterized by a marked reduction in size of the adult optic lobes and the central brain hemispheres. This is caused by the abnormal spacing of neuroblasts and a reduction in the production of neuronal progeny (Tejedor et al., 1995). At least seven closely related homologous mammalian kinases in the DYRK family have since been isolated (Guimera et al., 1996(Guimera et al., , 1999Shindoh et al., 1996;Song et al., 1996Song et al., , 1997Raich et al., 2003). The DYRK family possesses serine and threonine phosphorylation activity as well as autophosphorylation activity on tyrosine residues (Kentrup et al., 1996;Becker et al., 1998;Becker and Joost, 1999;Himpel et al., 2000). Their kinase activity is dependent on the YXY motif in the activation loop of the catalytic domain, which is located at the same position as the characteristic TXY motif of the mitogen-activated protein kinases (MAPKs), suggesting an activation mechanism similar to that of the MAPK (Himpel et al., 2000). Closely related enzymes in lower eukaryotes also have been isolated, including Yak1p in Saccharomyces cerevisiae (Garrett and Broach, 1989), Pom1p in Schizosaccharomyces pombe (Bahler and Pringle, 1998), and YakA in Dictyostelium discoideum (Van Es et al., 2001). Although not much is known about their cellular functions, they all seem to be involved in the regulation of the cell growth and/or development.In the DYRK family, DYRK1A has been the best characterized to date. The human Dyrk1A gene maps to the 21q22.2 region of chromosome 21, in the Down syndrome critical region (Rah...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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DYRK1A Enhances the Mitogen-activated Protein Kinase Cascade in PC12 Cells by Forming a Complex with Ras, B-Raf, and MEK1

Kelly

Rahmani

2005

MBoC

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“…We know that Dcaf7 also binds DYRK1A (32), a kinase that phosphorylates a wide range of proteins involved in metabolism, synaptic function, and neurodegeneration (33). Of greatest interest, DYRK1A maps to human chromosome 21 and perhaps is implicated in DS (34)(35)(36). We were interested in whether Hap1 and DYRK1A interact with Dcaf7 competitively or synergistically.…”

Section: Hap1 Stabilizes the Protein Level Of Dcaf7 By Inhibiting Itsmentioning

confidence: 99%

DYRK1A regulates Hap1–Dcaf7/WDR68 binding with implication for delayed growth in Down syndrome

Xiang

Ning

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Huntingtin-associated protein 1 (Hap1) is known to be critical for postnatal hypothalamic function and growth. Hap1 forms stigmoid bodies (SBs), unique neuronal cytoplasmic inclusions of unknown function that are enriched in hypothalamic neurons. Here we developed a simple strategy to isolate the SB-enriched fraction from mouse brain. By analyzing Hap1 immunoprecipitants from this fraction, we identified a Hap1-interacting SB component, DDB1 and CUL4 associated factor 7 (Dcaf7)/WD40 repeat 68 (WDR68), whose protein level and nuclear translocation are regulated by Hap1. Moreover, we found that Hap1 bound Dcaf7 competitively in cytoplasm with dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), a protein implicated in Down syndrome (DS). Depleting Hap1 promoted the DYRK1A-Dcaf7 interaction and increased the DYRK1A protein level. Transgenic DS mice overexpressing DYRK1A showed reduced Hap1-Dcaf7 association in the hypothalamus. Furthermore, the overexpression of DYRK1A in the hypothalamus led to delayed growth in postnatal mice, suggesting that DYRK1A regulates the Hap1-Dcaf7 interaction and postnatal growth and that targeting Hap1 or Dcaf7 could ameliorate growth retardation in DS.H untingtin-associated protein 1 (Hap1) is a cytoplasmic protein highly expressed in neurons of the CNS (1, 2). Hap1 was initially recognized for its binding to polyglutamine-expanded huntingtin (Htt), the protein responsible for Huntington's disease (3). Because Hap1 is expressed at various levels in different types of neurons (1,(4)(5)(6)(7)(8), it is likely involved in cell type-specific functions of the brain. For example, Hap1 is abundantly expressed in the hypothalamus, and its expression in the hypothalamus influences the central control of feeding (9); as a direct result, mice lacking Hap1 are malnourished and die in the early postnatal period (5, 10, 11). The function of Hap1 is also age dependent and appears to be important for postnatal neurogenesis in the paraventricular nuclei, the lateral hypothalamus (5, 11), and the dentate gyrus of the hippocampus (7).The specific function of Hap1 in the hypothalamus may be associated with unique cytoplasmic structures called "stigmoid bodies" (SBs), which are formed by Hap1 in the hypothalamus (12, 13) and appear to be non-membrane-bound, ovoid to circular in shape, and 0.5-3 μm in diameter (14,15). Widely regarded as a determinant marker for SBs, Hap1 is capable of sequestering several important disease-related proteins into SB-like inclusions in cell cultures, including Abelson helper integration site 1 (Ahi1), androgen receptor, TBP, and ataxin-3 (6, 16-18). However, in vivo evidence for such sequestration exists only for Ahi1, which is responsible for specific forms of Joubert syndrome. Other proteins, such as SorLA/LR11, sortilin, 5-HT 7 receptor, and 14-3-3, are also reported to be associated with . Although SBs are abundant in the hypothalamus, their functions remain elusive, despite speculation that they might be involved in sex-steroid maturation (15). We bel...

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“…By correlation of phenotype with genotype in patients with partial trisomies, this region has been defined as the "Down's syndrome critical region"; its triplication appears to be responsible for many features of Down's syndrome including mental retardation (4 -6). In sequencing projects of the Down's syndrome critical region, several groups have independently identified the human DYRK1 gene (7)(8)(9)(10)(11). Because of its high similarity with Drosophila MNB, DYRK1 is currently considered a candidate gene for the aberrant development of the brain that underlies mental retardation in Down's syndrome.…”

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confidence: 99%

Sequence Characteristics, Subcellular Localization, and Substrate Specificity of DYRK-related Kinases, a Novel Family of Dual Specificity Protein Kinases

Becker¹,

Weber²,

Wetzel³

et al. 1998

Journal of Biological Chemistry

266

269

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DYRK1 is a dual specificity protein kinase presumably involved in brain development. Here we show that the kinase belongs to a new family of protein kinases comprising at least seven mammalian isoforms (DYRK1A, DYRK1B, DYRK1C, DYRK2, DYRK3, DYRK4A, and DYRK4B), the yeast homolog Yak1p, and the Drosophila kinase minibrain (MNB). In rat tissues, DYRK1A is expressed ubiquitously, whereas transcripts for DYRK1B, DYRK2, DYRK3, and DYRK4 were detected predominantly in testes of adult but not prepuberal rats. 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. DYRK1A exhibited a punctate pattern of GFP fluorescence inside the nucleus and was co-purified with the nuclear matrix. Analysis of GFP-DYRK1A deletion constructs showed that the nuclear localization of DYRK1A was mediated by its nuclear targeting signal (amino acids 105-139) but that its characteristic subnuclear distribution depended on additional N-terminal elements (amino acids 1-104). When expressed in Escherichia coli, DYRK1A, DYRK2, DYRK3, MNB, and Yak1p catalyzed their autophosphorylation on tyrosine residues. The kinases differed in their substrate specificity in that DYRK2 and DYRK3, but not DYRK1A and MNB, catalyzed phosphorylation of histone H2B. The heterogeneity of their subcellular localization and substrate specificity suggests that the kinases are involved in different cellular functions.

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Cloning of a Human Homolog of theDrosophila Minibrain/Rat Dyrk Gene from “the Down Syndrome Critical Region” of Chromosome 21

Cited by 113 publications

References 0 publications

DYRK1A Enhances the Mitogen-activated Protein Kinase Cascade in PC12 Cells by Forming a Complex with Ras, B-Raf, and MEK1

DYRK1A Enhances the Mitogen-activated Protein Kinase Cascade in PC12 Cells by Forming a Complex with Ras, B-Raf, and MEK1

DYRK1A regulates Hap1–Dcaf7/WDR68 binding with implication for delayed growth in Down syndrome

Sequence Characteristics, Subcellular Localization, and Substrate Specificity of DYRK-related Kinases, a Novel Family of Dual Specificity Protein Kinases

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