Cell type- and brain structure-specific patterns of distribution of minibrain kinase in human brain

Węgiel, Jerzy; Kuchna, Izabela; Nowicki, Krzysztof; Frackowiak, Janusz; Dowjat, Karol; Silverman, Wayne; Reisberg, Barry; deLeon, Mony; Wısnıewskı, Thomas; Adayev, Tatyana; Chen-Hwang, Mo Chou; Hwang, Yu Wen

doi:10.1016/j.brainres.2004.03.008

Cited by 69 publications

(93 citation statements)

References 44 publications

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“…We were interested in whether Hap1 and DYRK1A interact with Dcaf7 competitively or synergistically. First, however, we wanted to examine the subcellular localization of DYRK1A, because studies have demonstrated both cytoplasmic and nuclear distribution of endogenous DYRK1A in neuronal cells, whereas ectopically expressed DYRK1A is found mainly in the nucleus (37)(38)(39)(40)(41). We found via subcellular fractionation and immunostaining that endogenous DYRK1A is localized predominantly in the cytoplasm in mouse brain in vivo and in cultured HEK293 and PC12 cells (Fig.…”

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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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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“…Although several groups have reported that DYRK1A is expressed in the adult mammalian brain in both neurons and astrocytes (29,30), this kinase has not been identified in astrocytic tumors. Given the strong effect of DYRK1A downregulation on glioma cell lines, we set out to explore the transcript levels of DYRK1A in normal tissue (obtained from surgery on epileptic patients) and in a panel of gliomas of different grades by quantitative RT-PCR (qRT-PCR).…”

Section: Dyrk1a Modulates Egfr Protein Levels and The Self-renewal Ofmentioning

confidence: 99%

Inhibition of DYRK1A destabilizes EGFR and reduces EGFR-dependent glioblastoma growth

Pozo

Zahonero²,

Fernández³

et al. 2013

J. Clin. Invest.

129

149

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Glioblastomas (GBMs) are very aggressive tumors that are resistant to conventional chemo-and radiotherapy. New molecular therapeutic strategies are required to effectively eliminate the subpopulation of GBM tumorinitiating cells that are responsible for relapse. Since EGFR is altered in 50% of GBMs, it represents one of the most promising targets; however, EGFR kinase inhibitors have produced poor results in clinical assays, with no clear explanation for the observed resistance. We uncovered a fundamental role for the dual-specificity tyrosine phosphorylation-regulated kinase, DYRK1A, in regulating EGFR in GBMs. We found that DYRK1A was highly expressed in these tumors and that its expression was correlated with that of EGFR. Moreover, DYRK1A inhibition promoted EGFR degradation in primary GBM cell lines and neural progenitor cells, sharply reducing the self-renewal capacity of normal and tumorigenic cells. Most importantly, our data suggest that a subset of GBMs depends on high surface EGFR levels, as DYRK1A inhibition compromised their survival and produced a profound decrease in tumor burden. We propose that the recovery of EGFR stability is a key oncogenic event in a large proportion of gliomas and that pharmacological inhibition of DYRK1A could represent a promising therapeutic intervention for EGFR-dependent GBMs.

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“…pCI-SI9/LI10 containing a tau minigene, SI9/LI10, comprising tau exons 9, 10, and 11, part of intron 9, and the full length of intron 10 has been described (23). Monoclonal antibody 8D9 was raised against a histidine-tagged protein containing the first 160 residues of rat Dyrk1A (24). The monoclonal anti-HA, anti-␣-tubulin, and anti-␤-actin were bought from Sigma.…”

Section: Methodsmentioning

confidence: 99%

Increased Dosage of Dyrk1A Alters Alternative Splicing Factor (ASF)-regulated Alternative Splicing of Tau in Down Syndrome

Shi

Zhang

Zhou

et al. 2008

Journal of Biological Chemistry

Self Cite

149

179

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Two groups of tau, 3R-and 4R-tau, are generated by alternative splicing of tau exon 10. Normal adult human brain expresses equal levels of them. Disruption of the physiological balance is a common feature of several tauopathies. Very early in their life, individuals with Down syndrome (DS) develop Alzheimer-type tau pathology, the molecular basis for which is not fully understood. Here, we demonstrate that Dyrk1A, a kinase encoded by a gene in the DS critical region, phosphorylates alternative splicing factor (ASF) at Ser-227, Ser-234, and Ser-238, driving it into nuclear speckles and preventing it from facilitating tau exon 10 inclusion. The increased dosage of Dyrk1A in DS brain due to trisomy of chromosome 21 correlates to an increase in 3R-tau level, which on abnormal hyperphosphorylation and aggregation of tau results in neurofibrillary degeneration. Imbalance of 3R-and 4R-tau in DS brain by Dyrk1A-induced dysregulation of alternative splicing factor-mediated alternative splicing of tau exon 10 represents a novel mechanism of neurofibrillary degeneration and may help explain early onset tauopathy in individuals with DS.The microtubule-associated protein tau plays an important role in the polymerization and stabilization of neuronal microtubules. Tau is thus crucial to both the maintenance of the neuronal cytoskeleton and the maintenance of the axonal transport. Abnormal hyperphosphorylation and accumulation of this protein into neurofibrillary tangles (NFTs) 2 in neurons, first discovered in Alzheimer disease (AD) brain (1, 2), is now known to be a characteristic of several related neurodegenerative disorders called tauopathies (3). Several different etiopathogenic mechanisms lead to development of NFTs (4). Adult human brain expresses six isoforms of tau from a single gene by alternative splicing of its pre-mRNA (5, 6). Inclusion or exclusion of exon 10 (E10), which codes for the second microtubule-binding repeat, divides tau isoforms into two main groups, three (3R)-or four (4R)-microtubule-binding repeat tau. They show key differences in their interactions with tau kinases as well as their biological function in the polymerization and stabilization of neuronal microtubules. In the adult human brain, 3R-tau and 4R-tau are expressed at similar levels (5, 7). Several specific mutations in the tau gene associated with frontotemporal dementias with Parkinsonism linked to chromosome 17 (FTDP-17) cause dysregulation of tau E10 splicing, leading to a selective increase in either 3R-tau or 4R-tau. It has therefore been suggested that equal levels of 3R-tau and 4R-tau may be critical for maintaining optimal neuronal physiology (8).Down syndrome (DS), caused by partial or complete trisomy of chromosome 21, is the most common chromosomal disorder and one of the leading causes of mental retardation in humans. Individuals with DS develop Alzheimer-type neurofibrillary degeneration as early as the fourth decade of life (9). The presence of Alzheimer-type amyloid pathology in DS is attributed to an extra copy of APP gen...

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Cell type- and brain structure-specific patterns of distribution of minibrain kinase in human brain

Cited by 69 publications

References 44 publications

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

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

Inhibition of DYRK1A destabilizes EGFR and reduces EGFR-dependent glioblastoma growth

Increased Dosage of Dyrk1A Alters Alternative Splicing Factor (ASF)-regulated Alternative Splicing of Tau in Down Syndrome

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