The Down syndrome-related protein kinase DYRK1A phosphorylates p27Kip1and Cyclin D1 and induces cell cycle exit and neuronal differentiation
Open accessAbstract
A fundamental question in neurobiology is how the balance between proliferation and differentiation of neuronal precursors is maintained to ensure that the proper number of brain neurons is generated. Substantial evidence implicates DYRK1A (dual specificity tyrosine-phosphorylation-regulated kinase 1A) as a candidate gene responsible for altered neuronal development and brain abnormalities in Down syndrome. Recent findings support the hypothesis that DYRK1A is involved in cell cycle control. Nonetheless, how DYRK1A contributes to neuronal cell cycle regulation and thereby affects neurogenesis remains poorly understood. In the present study we have investigated the mechanisms by which DYRK1A affects cell cycle regulation and neuronal differentiation in a human cell model, mouse neurons, and mouse brain. Dependent on its kinase activity and correlated with the dosage of overexpression, DYRK1A blocked proliferation of SH-SY5Y neuroblastoma cells within 24 h and arrested the cells in G₁ phase. Sustained overexpression of DYRK1A induced G₀ cell cycle exit and neuronal differentiation. Furthermore, we provide evidence that DYRK1A modulated protein stability of cell cycle-regulatory proteins. DYRK1A reduced cellular Cyclin D1 levels by phosphorylation on Thr286, which is known to induce proteasomal degradation. In addition, DYRK1A phosphorylated p27(Kip1) on Ser10, resulting in protein stabilization. Inhibition of DYRK1A kinase activity reduced p27(Kip1) Ser10 phosphorylation in cultured hippocampal neurons and in embryonic mouse brain. In aggregate, these results suggest a novel mechanism by which overexpression of DYRK1A may promote premature neuronal differentiation and contribute to altered brain development in Down syndrome.
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Overexpression of DYRK1A/Dyrk1a both in vivo and in vitro results in the nuclear export of Cyclin D1, reducing Cyclin D1 protein levels at multiple developmental ages in TgDyrk1a mice (E11.5 and E14.5).
“Overexpression of DYRK1A/Dyrk1a both in vivo and in vitro results in the nuclear export of Cyclin D1, resulting in reductions in Cyclin D1 protein levels at multiple developmental ages in TgDyrk1a mice (E11.5 & E14.5) (Najas et al., 2015; Park et al., 2010; Soppa et al., 2014; Yabut et al., 2010).”
From Sex-specific developmental alterations in DYRK1A expression in the brain of a Down syndrome mouse model (2024) · cites this paper as Soppa et al., 2014
The Results section (page not provided) reports that DYRK1A overexpression reduced Cyclin D1 protein levels in cultured SH-SY5Y cells. The Discussion reports nuclear export in neuronal cells as a finding from an earlier study. This paper does not establish that overexpression caused Cyclin D1 export or reduced its levels in TgDyrk1a mice at E11.5 and E14.5. (LLM, conf=0.88)
Experimental — accuracy not yet measuredDYRK1A/Dyrk1a overexpression results in more cells in the G1/0 phase versus S or G2/M phase, leading to cell proliferation deficits, premature cell exit and differentiation, and the nuclear export of Cyclin D1.
“In addition, DYRK1A/Dyrk1a overexpression results in more cells in the G1/0 phase versus S or G2/M phase, leading to cell proliferation deficits, premature cell exit and differentiation, and the nuclear export of Cyclin D1 (Najas et al., 2015; Soppa et al., 2014).”
From Sex-specific developmental alterations in DYRK1A expression in the brain of a Down syndrome mouse model (2024) · cites this paper as Soppa et al., 2014
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MethodAkt-dependent Phosphorylation of p27Kip1Promotes Binding to 14-3-3 and Cytoplasmic Localization
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“Cells that have exited the cell cycle can be detected by their reduced RNA content.(35,36) To test the hypothesis that DYRK1A overexpression induces cell cycle exit of SH-SY5Y cells, we overexpressed DYRK1A for 5 d and performed 2-dimensional FACS analyses of cellular RNA and DNA contents (Fig.”
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BackgroundCell cycle control of mammalian neural stem cells: putting a speed limit on G1
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Harmine specifically inhibits protein kinase DYRK1A and interferes with neurite formation
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Neurogenesis and the Cell Cycle
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“Consistent with previous reports that DYRK1A acts as a negative regulator of apoptosis and a positive regulator of cell survival, DYRK1A overexpression did not result in enhanced cell death of SH-SY5Y cells.(58,59) Long-term overexpression of DYRK1A increased a population of SH-SY5Y cells with reduced cellular DNA and…”
ResultDYRK1A BAC transgenic mice show altered synaptic plasticity with learning and memory defects
Ahn, K.-J., Jeong, H. K., Choi, H.-S., Ryoo, S.-R., Kim, Y. J., Goo, J.-S., Choi, S.-Y., Han, J.-S., Ha, I., & Song, W.-J. (2006) · Neurobiology of Disease · doi:10.1016/j.nbd.2005.12.006 · Cited by 220 · see citing works
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BackgroundSelf-citationPhosphorylation at Serine 10, a Major Phosphorylation Site of p27 , Increases Its Protein Stability
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“Here we show that DYRK1A increased p27 protein levels in SH-SY5Y cells by phosphorylation at Ser10, a phosphorylation site known to induce p27 stabilization.(9,63) Interestingly, phosphorylation of p27 on Ser10 in neural stem cells has been shown to be correlated with cell cycle exit and progression to neuronal differ…”
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“SH-SY5Y cells overexpressing DYRK1A were treated with either the GSK3β inhibitor CHIR99021 or the DYRK1A inhibitor leucettine L41.”
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“5-fold overexpressed in Down syndrome.(17,18) Evidence from transgenic mouse models as well as studies in chicken and Drosophila (where the DYRK1A orthologs are termed Minibrain) have revealed that both overexpression and reduced expression of DYRK1A result in neurodevelopmental alterations due to deregulation of neur…”
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“5-fold overexpressed in Down syndrome.(17,18) Evidence from transgenic mouse models as well as studies in chicken and Drosophila (where the DYRK1A orthologs are termed Minibrain) have revealed that both overexpression and reduced expression of DYRK1A result in neurodevelopmental alterations due to deregulation of neur…”
BackgroundCyclin D1 and CDK4 Activity Contribute to the Undifferentiated Phenotype in Neuroblastoma
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“DYRK1A phosphorylates p27 at Ser10 and Cyclin D1 at Thr286 Cell cycle exit and differentiation of neural precursors are regulated by p27 and Cyclin D/CDK complexes.(1,3,62) Here we show that DYRK1A increased p27 protein levels in SH-SY5Y cells by phosphorylation at Ser10, a phosphorylation site known to induce p27 sta…”
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“A strong dosage effect of the human DYRK1A gene was further substantiated by the identification of patients with heterozygous loss-of-function mutations of the DYRK1A gene, who develop a severe syndrome of intellectual disability and microcephaly.(20,21) Importantly, impaired balance between proliferation and cell cyc…”
BackgroundThe non‐apoptotic role of p53 in neuronal biology: enlightening the dark side of the moon
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“Another substrate of DYRK1A that may contribute to neuronal cell cycle regulation and differentiation is p53.(54,73) Phosphorylation at Ser15 by DYRK1A enhances expression of p53 target genes such as the CDK inhibitor p21 and thereby attenuates G 1 –S phase transition.”
BackgroundNeuronal differentiation and long-term culture of the human neuroblastoma line SH-SY5Y
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“Therefore they are well established as a cell model for neurobiological questions.(32,33,38,57) Here we show that DYRK1A suppressed proliferation of SH-SY5Y cells in a dose- and kinase activity-dependent manner.”
BackgroundMethodYabut, O., Domogauer, J., & D’Arcangelo, G. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.4711-09.2010 · Cited by 154 · cited 2× · see citing works
“This finding supports the validity of our cell model, since DYRK1A overexpression has previously been reported to attenuate the proliferation of neural progenitors in the developing mouse cerebral cortex and neural precursor cells derived from human embryonic stem cells.(29,54) The majority of SH-SY5Y cells ceased pro…”
BackgroundResultRetinoic acid, a regeneration‐inducing molecule
Maden, M., & Hind, M. D. (2003) · Developmental Dynamics · doi:10.1002/dvdy.10222 · Cited by 152 · see citing works
Chen, J.-Y., Lin, J.-R., Tsai, F.-C., & Meyer, T. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.09.009 · Cited by 144 · cited 10× · see citing works
“This effect was also observed in previous studies involving transient or stable overexpression of DYRK1A and DYRK1A-KR.(40,41) Nevertheless, our results of gradual overexpression allow the comparison of DYRK1A and DYRK1A-KR at similar expression levels and support the conclusion that the effect of DYRK1A depends on it…”
BackgroundResultInfluentialThe Cyclin-dependent Kinase Inhibitor p27Kip1 Is Stabilized in G0 by Mirk/dyrk1B Kinase
Deng, X., Mercer, S. E., Shah, S., Ewton, D. Z., & Friedman, E. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m400479200 · Cited by 144 · cited 2× · see citing works
“Harmine, EGCG, and leucettine L41 have been profiled against large panels of protein kinases(47) and do not inhibit the other kinases that are known to phosphorylate p27 at Ser10 (KIS, AKT, CDK5, HIPK2)(11-14,49) except for DYRK1B, which is a regulator of p27 in cancer cells.(15,50) All 3 DYRK1A inhibitors substantial…”
BackgroundMethodHämmerle, B., Ulin, E., Guimera, J., Becker, W., Guillemot, F., & Tejedor, F. J. (2011) · Development · doi:10.1242/dev.066167 · Cited by 137 · cited 2× · see citing works
“Moreover, we have previously reported that DYRK1A coordinates cell cycle exit and differentiation of neuronal precursors.(31) Nonetheless, the mechanistic network by which DYRK1A contributes to the regulation of cell cycle withdrawal and differentiation of neuronal precursors is still poorly understood.”
BackgroundMethodSelf-citationDyrk1A phosphorylates p53 and inhibits proliferation of embryonic neuronal cells
Park, J., Oh, Y., Yoo, L., Jung, M.-S., Song, W.-J., Lee, S.-H., Seo, H., & Chung, K. C. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.147520 · Cited by 134 · cited 3× · see citing works
“This finding supports the validity of our cell model, since DYRK1A overexpression has previously been reported to attenuate the proliferation of neural progenitors in the developing mouse cerebral cortex and neural precursor cells derived from human embryonic stem cells.(29,54) The majority of SH-SY5Y cells ceased pro…”
BackgroundResultSeifert, A., Allan, L. A., & Clarke, P. R. (2008) · FEBS Journal · doi:10.1111/j.1742-4658.2008.06751.x · Cited by 132 · cited 1× · see citing works
“Consistent with previous reports that DYRK1A acts as a negative regulator of apoptosis and a positive regulator of cell survival, DYRK1A overexpression did not result in enhanced cell death of SH-SY5Y cells.(58,59) Long-term overexpression of DYRK1A increased a population of SH-SY5Y cells with reduced cellular DNA and…”
ResultPost-translational regulation of the tumor suppressor p27KIP1
Vervoorts, J., & Lüscher, B. (2008) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-008-8296-7 · Cited by 131 · see citing works
Mirk/dyrk1B Kinase Destabilizes Cyclin D1 by Phosphorylation at Threonine 288
Zou, Y., Ewton, D. Z., Deng, X., Mercer, S. E., & Friedman, E. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m403042200 · Cited by 123 · cited 3× · see citing works
“Phosphorylation of Cyclin D1 on Thr286 induces the ubiquitinylation by the Skp1-Cul1-F box (SCF) ubiquitin ligase and subsequent proteasomal degradation.67 Although GSK3β was initially reported to phosphorylate Cyclin D1 on Thr286,68 DYRK1B was later proposed to promote Cyclin D1 degradation by phosphorylation at Thr2…”
BackgroundCourcet, J.-B., Faivre, L., Malzac, P., Masurel-Paulet, A., Lopez, E., Callier, P., Lambert, L., Lemesle, M., Thevenon, J., Gigot, N., et al. (2012) · Journal of Medical Genetics · doi:10.1136/jmedgenet-2012-101251 · Cited by 121 · cited 1× · see citing works
“A strong dosage effect of the human DYRK1A gene was further substantiated by the identification of patients with heterozygous loss-of-function mutations of the DYRK1A gene, who develop a severe syndrome of intellectual disability and microcephaly.(20,21) Importantly, impaired balance between proliferation and cell cyc…”
BackgroundFrank, C. L., & Tsai, L.-H. (2009) · Neuron · doi:10.1016/j.neuron.2009.03.029 · Cited by 118 · see citing works
Godin, J. D., Thomas, N., Laguesse, S., Malinouskaya, L., Close, P., Malaise, O., Purnelle, A., Raineteau, O., Campbell, K., Fero, M. L., et al. (2012) · Developmental Cell · doi:10.1016/j.devcel.2012.08.006 · Cited by 109 · cited 1× · see citing works
“Consistently, beyond its function as an inhibitor of CDK activity in the nucleus, p27 is also thought to be a cytosolic mediator of neuronal differentiation, microtubule polymerization, and migration.(7,34,66) Here we propose that DYRK1A overexpression promotes neuronal differentiation by increasing p27 levels through…”
BackgroundBecker, W. B. (2012) · Cell Cycle · doi:10.4161/cc.21404 · Cited by 104 · cited 2× · see citing works
“DYRK1A in neuronal cell cycle regulation The observation that DYRK1A regulates protein turnover of p27 and Cyclin D1 in neuronal cells is in accordance with numerous previous reports that kinases of the DYRK family function as regulators of protein stability in cell cycle control.(27) Figure 8.”
BackgroundResultSelf-citationDYRK1A: a potential drug target for multiple down syndrome neuropathologies
Becker, W., Soppa, U., & Tejedor, F. (2014) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/18715273113126660186 · Cited by 103 · cited 1× · see citing works
“In order to assess whether DYRK1A contributes to p27 Ser10 phosphorylation in differentiating brain neurons, we cultured E12 embryos for 6 h in the presence of EGCG, harmine, and leucettine L41, 3 different and chemically unrelated DYRK1A inhibitors.(47) This time period is substantially shorter than the duration of a…”
MethodSelf-citationCoupling Cell Cycle Exit, Neuronal Differentiation and Migration in Cortical Neurogenesis
Nguyen, L., Besson, A., Roberts, J. M., & Guillemot, F. (2006) · Cell Cycle · doi:10.4161/cc.5.20.3381 · Cited by 100 · cited 1× · see citing works
“Consistently, beyond its function as an inhibitor of CDK activity in the nucleus, p27 is also thought to be a cytosolic mediator of neuronal differentiation, microtubule polymerization, and migration.(7,34,66) Here we propose that DYRK1A overexpression promotes neuronal differentiation by increasing p27 levels through…”
BackgroundMitsuhashi, T., Aoki, Y., Ekşioğlu, Y. Z., Takahashi, T., Bhide, P. G., Reeves, S. A., & Caviness, V. S. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.111051398 · Cited by 97 · cited 1× · see citing works
“Overexpression of p27 has been shown to lengthen G 1 phase of neural progenitor cells in the mouse embryo.(65) However, we detected p27 Ser10 phosphorylation primarily in early differentiating neurons but not in the ventricular zone of mouse telencephalon, where neural progenitors and newborn neuronal precursors are l…”
BackgroundRetinoids and the control of growth/death decisions in human neuroblastoma cell lines
Melino, G., Thiele, C. J., Knight, R. A., & Piacentini, M. (1997) · Journal of Neuro-Oncology · doi:10.1023/a:1005733430435 · Cited by 90 · cited 1× · see citing works
“35 Here, these cells may represent the intermediate and substrate type (I- and S-type) of SH-SY5Y cells that exit cell cycle but do not develop the characteristics of the neuroblastic cell type (N-type).(37) These results show that longterm overexpression of DYRK1A not only prevents S-phase entry of SH-SY5Y neuroblast…”
BackgroundKelly, P. A., & Rahmani, Z. (2005) · Molecular Biology of the Cell · doi:10.1091/mbc.e04-12-1085 · Cited by 86 · cited 1× · see citing works
“We and others have previously shown that DYRK1A overexpression enhances neurite outgrowth in rat PC12 cells and that DYRK1A inhibition interferes with neurite formation of mouse hippocampal neurons.(28,30,44) Consistent with our previous findings in the developing vertebrate central nervous system,(31) our present res…”
ResultHämmerle, B., Elizalde, C., & Tejedor, F. J. (2008) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2008.06092.x · Cited by 82 · cited 1× · see citing works
“We used mouse whole-embryo cultures (E12), where all relevant neurodevelopmental stages are coexisting and DYRK1A is highly expressed in the telencephalon.(45) As shown in Figure 10, most of pSer10 p27 immunostaining in E12 embryonic mouse brain was overlapping with that of β-III-tubulin (TUJ1), a well-known marker of…”
MethodSelf-citationAshford, A. L., Oxley, D., Kettle, J. G., Hudson, K., Guichard, S. M., Cook, S. J., & Lochhead, P. A. (2013) · Biochemical Journal · doi:10.1042/bj20130461 · Cited by 81 · cited 6× · see citing works
“Two recent reports have now made clear that either DYRK1A or DYRK1B can promote Cyclin D1 degradation via direct phosphorylation of Thr286 but do not target Thr288.(16,41) Consistent with our results for the effect of DYRK1A in SH-SY5Y cells, Ashford et al.”
BackgroundResultInfluentialThe MNB/DYRK1A protein kinase: Neurobiological functions and Down syndrome implications
Hämmerle, B., Elizalde, C., Galcerán, J., Becker, W. B., & Tejedor, F. J. (2003) · Journal of neural transmission. Supplementum · doi:10.1007/978-3-7091-6721-2_11 · Cited by 81 · see citing works
Self-citationCo-ordination of cell cycle and differentiation in the developing nervous system
Hindley, C., & Philpott, A. (2012) · Biochemical Journal · doi:10.1042/bj20112040 · Cited by 76 · cited 1× · see citing works
“DYRK1A phosphorylates p27 at Ser10 and Cyclin D1 at Thr286 Cell cycle exit and differentiation of neural precursors are regulated by p27 and Cyclin D/CDK complexes.(1,3,62) Here we show that DYRK1A increased p27 protein levels in SH-SY5Y cells by phosphorylation at Ser10, a phosphorylation site known to induce p27 sta…”
BackgroundCuende, J., Moreno, S., Bolaños, J. P., & Almeida, Á. (2008) · Oncogene · doi:10.1038/sj.onc.1210987 · Cited by 70 · cited 4× · see citing works
“The majority of SH-SY5Y cells ceased proliferation and arrested in G 1 phase after 24 h of DYRK1A overexpression, whereas RA arrests the cell cycle of SH-SY5Y cells in a delayed manner after at least 2–3 d.(32) Therefore, our results indicate a direct effect of DYRK1A on the current G 1 -phase once expression levels a…”
BackgroundMethodInfluentialMirk Regulates the Exit of Colon Cancer Cells from Quiescence
Jin, K., Ewton, D. Z., Park, S., Hu, J., & Friedman, E. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.035519 · Cited by 61 · cited 1× · see citing works
“Harmine, EGCG, and leucettine L41 have been profiled against large panels of protein kinases(47) and do not inhibit the other kinases that are known to phosphorylate p27 at Ser10 (KIS, AKT, CDK5, HIPK2)(11-14,49) except for DYRK1B, which is a regulator of p27 in cancer cells.(15,50) All 3 DYRK1A inhibitors substantial…”
BackgroundMiyata, Y., & Nishida, E. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2011.06.023 · Cited by 60 · see citing works
Increased dosage of DYRK1A and DSCR1 delays neuronal differentiation in neocortical progenitor cellsPreprint
Kurabayashi, N., & Sanada, K. (2013) · Genes & Development · doi:10.1101/gad.226381.113 · Cited by 57 · see citing works
Kawauchi, T., Shikanai, M., & Kosodo, Y. (2013) · Genes to Cells · doi:10.1111/gtc.12029 · Cited by 47 · see citing works
Retinoic Acid Induces p27Kip1 Nuclear Accumulation by Modulating Its Phosphorylation
Borriello, A., Cucciolla, V., Criscuolo, M., Indaco, S., Oliva, A., Giovane, A., Bencivenga, D., Iolascon, A., Zappia, V., & Ragione, F. D. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-2759 · Cited by 40 · cited 1× · see citing works
“In addition, phosphorylation of Ser10 by an unidentified protein kinase has previously been reported to account for the increased half-life and accumulation of p27 during RA-induced differentiation of neuroblastoma cells.(64) In SH-SY5Y cells, phosphorylation and stabilization of p27 were well correlated with the time…”
BackgroundTransferring genes into cultured mammalian embryos by electroporation
Takahashi, M. P., Nomura, T., & Osumi, N. (2008) · Development Growth & Differentiation · doi:10.1111/j.1440-169x.2008.01046.x · Cited by 39 · cited 2× · see citing works
“Dissection and culture of mouse embryos was performed essentially as described by Takahashi et al.78 E12 embryos were cultured in the presence or absence of the DYRK1A inhibitors harmine (4 μM), EGCG (10 μM), leucettine L41 (8 μM) or without inhibitor for 6 h.”
MethodZheng, Y.-L., Li, B., Rudrabhatla, P., Shukla, V., Amin, N. D., Maric, D., Kesavapany, S., Kanungo, J., Pareek, T. K., Takahashi, S., et al. (2010) · Molecular Biology of the Cell · doi:10.1091/mbc.e10-01-0054 · Cited by 37 · cited 1× · see citing works
“Interestingly, phosphorylation of p27 on Ser10 in neural stem cells has been shown to be correlated with cell cycle exit and progression to neuronal differentiation and neurite outgrowth.(49) In addition, phosphorylation of Ser10 by an unidentified protein kinase has previously been reported to account for the increas…”
BackgroundStefos, G., Soppa, U., Dierssen, M., & Becker, W. (2013) · PLoS ONE · doi:10.1371/journal.pone.0067470 · Cited by 20 · cited 2× · see citing works
“Lentivirus production was performed as described.(30) Co-transduction of SH-SY5Y cells then was titrated with different amounts of FUW-tetONGFP-DYRK1A/KR and FUW-M2rtTA containing lentivirus until achieving maximal transduction efficiency as controlled by doxycycline-induced GFP fluorescence.”
MethodResultSelf-citationSandoval, R., Pilkinton, M. A., & Colamonici, O. R. (2009) · Experimental Cell Research · doi:10.1016/j.yexcr.2009.07.014 · Cited by 17 · cited 2× · see citing works
“For example, it is conceivable that DYRK1A induced depletion of nuclear Cyclin D1 promotes DREAM complex formation by reducing CyclinD/CDK4-dependent phosphorylation of p130/ RBL2.”
Background
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Targeting Cancer Cell Dormancy
Recasens, A., & Munoz, L. (2019) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2018.12.004 · Cited by 356 · see citing works
Inhibition of DYRK1A Stimulates Human β-Cell Proliferation
Dirice, E., Walpita, D., Vetere, A., Meier, B. C., Kahraman, S., Hu, J., Dančík, V., Burns, S. M., Gilbert, T. J., Olson, D. E., et al. (2016) · Diabetes · doi:10.2337/db15-1127 · Cited by 205 · see citing works
“Recent evidence showed that DYRK1A phosphorylates the cell cycle inhibitor p27, and that DYRK1A overexpression blocked cell proliferation (39); therefore, we tested the effects of 5-IT and harmine on rat INS-1E cells.”
BackgroundStem Cell Plasticity and Dormancy in the Development of Cancer Therapy Resistance
Angelis, M. L. D., Francescangeli, F., Torre, F. L., & Zeuner, A. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.00626 · Cited by 203 · see citing works
Duchon, A., & Herault, Y. (2016) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2016.00104 · Cited by 181 · see citing works
“DYRK1A regulates proliferation and neuronal differentiation through the phosphorylation of p27Kip1 and Cyclin D1 (CCND1) (Hammerle et al., 2011; Soppa et al., 2014).”
BackgroundAngelis, M. L. D., Francescangeli, F., & Zeuner, A. (2019) · Cancers · doi:10.3390/cancers11101569 · Cited by 176 · see citing works
“The maintenance of dormancy has also been experimentally achieved by increasing the expression of dormancy-related factors, including p38 MAPK [172], DYRK1A [182,183], and N2RF1 [174,178].”
BackgroundDYRK1A and cognition: A lifelong relationship
Arbonés, M. L., Thomazeau, A., Nakano-Kobayashi, A., Hagiwara, M., & Delabar, J. M. (2018) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2018.09.010 · Cited by 165 · see citing works
“…cells, the overexpression of DYRK1A induces cell cycle exit and neuronal differentiation, an effect that correlates with increased phosphorylation of Cyclin D1 on Thr286, which promotes degradation of the protein, and of p27Kip1 in Ser10, an event that stabilizes the protein (Soppa et al., 2014).”
BackgroundAutism spectrum disorder and epilepsy: Disorders with a shared biology
Lee, B. H., Smith, T., & Paciorkowski, A. R. (2015) · Epilepsy & Behavior · doi:10.1016/j.yebeh.2015.03.017 · Cited by 167 · see citing works
“In mouse models, Dyrk1A has been shown to play important roles in cell cycle control [48] and synaptic plasticity [49].”
BackgroundErnst, C. (2016) · Trends in Neurosciences · doi:10.1016/j.tins.2016.03.001 · Cited by 145 · see citing works
Neocortical neurogenesis and the etiology of autism spectrum disorder
Packer, A. (2016) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2016.03.002 · Cited by 138 · see citing works
Chromatin-wide Profiling of DYRK1A Reveals a Role as a Gene-Specific RNA Polymerase II CTD Kinase
Vona, C. D., Bezdan, D., Islam, A. B. M. M. K., Salichs, E., López-Bigas, N., Ossowski, S., & de la Luna, S. (2015) · Molecular Cell · doi:10.1016/j.molcel.2014.12.026 · Cited by 129 · see citing works
“512 Molecular Cell 57, 506–520, February 5, 2015 a2015 Elsevier Inc cules regulating cell-cycle progression (Chen et al., 2013; Litovchick et al., 2011; Soppa et al., 2014), and hence, we assessed the transcriptional activation of DYRK1A target genes in proliferating and serum-starved T98G cells.”
BackgroundJarhad, D. B., Mashelkar, K. K., Kim, H., Noh, M., & Jeong, L. S. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b00185 · Cited by 136 · see citing works
DYRK1A inhibitors for disease therapy: Current status and perspectives
Liu, T., Wang, Y., Wang, J., Ren, C., Chen, H., & Zhang, J. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.114062 · Cited by 126 · see citing works
Zebrafish knockout of Down syndrome gene, DYRK1A, shows social impairments relevant to autism
Kim, O.-H., Cho, H.-J., Han, E., Hong, T. I., Ariyasiri, K., Choi, J. H., Hwang, K.-S., Jeong, Y.-M., Yang, S.-Y., Yu, K., et al. (2017) · Molecular Autism · doi:10.1186/s13229-017-0168-2 · Cited by 123 · see citing works
“Since DYRK1A is known to play key roles in cell proliferation, survival, and differentiation during neurogenesis in mouse models [16, 42], we tested the expression of the neural stem cell marker, sox2, and the neuronal determination marker, neurog1, by whole-mount in situ hybridization.”
Neurogenesis impairment: An early developmental defect in Down syndrome
Stagni, F., Giacomini, A., Emili, M., Guidi, S., & Bartesaghi, R. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2017.07.026 · Cited by 120 · see citing works
DYRK1A: the double-edged kinase as a protagonist in cell growth and tumorigenesis
Fernández, P., Zahonero, C., & Sánchez‐Gómez, P. (2015) · Molecular & Cellular Oncology · doi:10.4161/23723548.2014.970048 · Cited by 110 · see citing works
The DYRK Family of Kinases in Cancer: Molecular Functions and Therapeutic Opportunities
Boni, J., Rubio-Pérez, C., López-Bigas, N., Fillat, C., & de la Luna, S. (2020) · Cancers · doi:10.3390/cancers12082106 · Cited by 109 · see citing works
“The link between DYRK1A and cell proliferation is based on its ability to phosphorylate crucial cell cycle regulators, like Cyclin D proteins or p27 (Figure 3 and Table 1), modulating their stability and, hence, their cellular levels [50,53,58,78].”
BackgroundBronicki, L. M., Redin, C., Drunat, S., Piton, A., Lyons, M., Passemard, S., Baumann, C., Faivre, L., Thevenon, J., Rivière, J.-B., et al. (2015) · European Journal of Human Genetics · doi:10.1038/ejhg.2015.29 · Cited by 105 · see citing works
DYRK1A: a down syndrome-related dual protein kinase with a versatile role in tumorigenesis
Laham, A., Saber-Ayad, M., & El-Awady, R. (2020) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-020-03626-4 · Cited by 1 · see citing works
Najas, S., Arranz, J., Lochhead, P. A., Ashford, A. L., Oxley, D., Delabar, J. M., Cook, S. J., Barallobre, M. J., & Arbonés, M. L. (2015) · EBioMedicine · doi:10.1016/j.ebiom.2015.01.010 · Cited by 92 · see citing works
“, 2010) and p27 levels (Soppa et al., 2014) in cell culturemodels we observed no change in the levels of these proteins in TgDyrk1a embryos.”
BackgroundResultInfluentialDYRK1A regulates B cell acute lymphoblastic leukemia through phosphorylation of FOXO1 and STAT3
Bhansali, R. S., Rammohan, M., Lee, P., Laurent, A. P., Wen, Q., Suraneni, P. K., Yip, B. H., Tsai, Y.-C., Jenni, S., Bornhauser, B. C., et al. (2021) · Journal of Clinical Investigation · doi:10.1172/jci135937 · Cited by 92 · see citing works
Nguyen, T. L., Duchon, A., Manousopoulou, A., Loaëc, N., Villiers, B., Pani, G., Karatas, M., Mechling, A. E., Harsan, L. A., Limanton, E., et al. (2018) · Disease Models & Mechanisms · doi:10.1242/dmm.035634 · Cited by 87 · see citing works
Thompson, B. J., Bhansali, R. S., Diebold, L. P., Cook, D. E., Stolzenburg, L. R., Casagrande, A.-S., Besson, T., Leblond, B., Désiré, L., Malinge, S., et al. (2015) · The Journal of Experimental Medicine · doi:10.1084/jem.20150002 · Cited by 83 · see citing works
“However, equally compelling studies have shown that DYRK1A suppresses proliferation (Hämmerle et al., 2011; Liu et al., 2014; Soppa et al., 2014), lengthens the time to cell cycle reentry (Chen et al., 2013), and promotes quiescence (Litovchick et al., 2011; Forristal et al., 2014).”
BackgroundInfluentialA TOR-YAK1 signaling axis controls cell cycle, meristem activity and plant growth in Arabidopsis
Barrada, A., Djendli, M., Desnos, T., Mercier, R., Robaglia, C., Montané, M., & Menand, B. (2019) · Development · doi:10.1242/dev.171298 · Cited by 83 · see citing works
“…mutations Arabidopsis YAK1 was previously reported as the homolog of human/Drosophila DYRK1A/Minibrain (Aranda et al., 2011; Karpov et al., 2014), an essential regulator of cell cycle exit in the central nervous system and a contributor to Down syndrome (Najas et al., 2015; Soppa et al., 2014).”
BackgroundAtas-Ozcan, H., Brault, V., Duchon, A., & Herault, Y. (2021) · Genes · doi:10.3390/genes12111833 · Cited by 78 · see citing works
“This cell cycle exit is triggered by upregulation of the cy lin-dependent kinase inhibitor p27KIP1 (CDKN1B) [79], which was achi ved by its phosphorylation by DYRK1A t Ser10 leading to its stabilization [80].”
BackgroundInfluentialLee, P., Bhansali, R. S., Izraeli, S., Hijiya, N., & Crispino, J. D. (2016) · Leukemia · doi:10.1038/leu.2016.164 · Cited by 73 · see citing works
Soppa, U., & Becker, W. B. (2015) · Current Biology · doi:10.1016/j.cub.2015.02.067 · Cited by 71 · see citing works
Self-citationThe Omnipresence of DYRK1A in Human Diseases
Deboever, E., Fistrovich, A., Hulme, C., & Dunckley, T. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23169355 · Cited by 77 · see citing works
Sato, K., Padgaonkar, A., Baker, S. J., Cosenza, S. C., Rechkoblit, O., Subbaiah, D. R. C. V., Domenech, J. M. D., Bartkowski, A., Port, E. R., Aggarwal, A. K., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-24878-z · Cited by 70 · see citing works
CC-401 Promotes β-Cell Replication via Pleiotropic Consequences of DYRK1A/B Inhibition
Abdolazimi, Y., Zhao, Z., Lee, S., Xu, H., Allegretti, P. A., Horton, T. M., Yeh, B. T., Moeller, H. P., Nichols, R. J., McCutcheon, D., et al. (2018) · Endocrinology · doi:10.1210/en.2018-00083 · Cited by 68 · see citing works
Rammohan, M., Harris, E., Bhansali, R. S., Zhao, E., Li, L. S., & Crispino, J. D. (2022) · Oncogene · doi:10.1038/s41388-022-02245-6 · Cited by 68 · see citing works
A wake‐up call to quiescent cancer cells – potential use of DYRK 1B inhibitors in cancer therapy
Becker, W. B. (2017) · FEBS Journal · doi:10.1111/febs.14347 · Cited by 71 · see citing works
Self-citationDyrk1a regulates the cardiomyocyte cell cycle via D-cyclin-dependent Rb/E2f-signalling
Hille, S. S., Dierck, F., Kühl, C., Sosna, J., Adam‐Klages, S., Adam, D., Lüllmann‐Rauch, R., Frey, N., & Kühn, C. (2016) · Cardiovascular Research · doi:10.1093/cvr/cvw074 · Cited by 66 · see citing works
Nguyen, T. L., Fruit, C., Hérault, Y., Meijer, L., & Besson, T. (2017) · Expert Opinion on Therapeutic Patents · doi:10.1080/13543776.2017.1360285 · Cited by 67 · see citing works
Rüben, K., Wurzlbauer, A., Walte, A., Sippl, W., Bracher, F., & Becker, W. B. (2015) · PLoS ONE · doi:10.1371/journal.pone.0132453 · Cited by 65 · see citing works
Self-citationNitrogen-dependent coordination of cell cycle, quiescence and TAG accumulation in Chlamydomonas
Takeuchi, T., & Benning, C. (2019) · Biotechnology for Biofuels · doi:10.1186/s13068-019-1635-0 · Cited by 63 · see citing works
Glenewinkel, F., Cohen, M. J., King, C. R., Kaspar, S., Bamberg‐Lemper, S., Mymryk, J. S., & Becker, W. B. (2016) · Scientific Reports · doi:10.1038/srep28241 · Cited by 63 · see citing works
Self-citationDYRK1A overexpression enhances STAT activity and astrogliogenesis in a Down syndrome mouse model
Kurabayashi, N., Nguyen, M. D., & Sanada, K. (2015) · EMBO Reports · doi:10.15252/embr.201540374 · Cited by 57 · see citing works
“Together with the impaired proliferation of progenitors [36,37], these events may contribute to reduced neuronal production and increased astroglial generation in DS.”
BackgroundLoaëc, N., Attanasio, E., Villiers, B., Durieu, É., Tahtouh, T., Cam, M., Davis, R. A., Alencar, A., Roué, M., Bourguet‐Kondracki, M., et al. (2017) · Marine Drugs · doi:10.3390/md15100316 · Cited by 57 · see citing works
“SH-SY5Y cells conditionally expressing human DYRK1A [36], under the control of doxycycline (gift from Dr.”
BackgroundMethodMenon, V., Ananthapadmanabhan, V., Swanson, S. K., Saini, S., Sesay, F. F., Yakovlev, V. A., Florens, L. A., DeCaprio, J. A., Washburn, M. P., Dozmorov, M. G., et al. (2019) · Cell Cycle · doi:10.1080/15384101.2019.1577525 · Cited by 53 · see citing works
“DYRK1A preferentially phosphorylates protein substrates that match the consensus R-X(XX)-S-P where X is any amino acid [22,23] although some substrates such as cyclin D1 contain alternative phosphorylation sites [18,19].”
BackgroundDYRK1A-haploinsufficiency in mice causes autistic-like features and febrile seizures
Raveau, M., Shimohata, A., Amano, K., Miyamoto, H., & Yamakawa, K. (2017) · Neurobiology of Disease · doi:10.1016/j.nbd.2017.12.003 · Cited by 49 · see citing works
“Among the main roles identified so far, Dyrk1a regulates the cell cycle, differentiation and arborization of neuronal cells, vesicle trafficking and neurotransmission (Dang et al., 2017; Grau et al., 2014; Hämmerle et al., 2011; Ori-McKenney et al., 2016; Park et al., 2012; Soppa et al., 2014).”
BackgroundGlobal phosphoproteomics reveals DYRK1A regulates CDK1 activity in glioblastoma cells
Recasens, A., Humphrey, S. J., Ellis, M., Hoque, M., Abbassi, R. H., Chen, B., Longworth, M., Needham, E. J., James, D. E., Johns, T. G., et al. (2021) · Cell Death Discovery · doi:10.1038/s41420-021-00456-6 · Cited by 52 · see citing works
Luco, S. M., Pohl, D., Sell, E., Wagner, J. D., Dyment, D. A., & Daoud, H. (2016) · BMC Medical Genetics · doi:10.1186/s12881-016-0276-4 · Cited by 49 · see citing works
“It encodes a highly conserved protein that plays an essential role in the development of the central nervous system [2–4].”
BackgroundIncreased dosage of DYRK1A leads to congenital heart defects in a mouse model of Down syndrome
Lana‐Elola, E., Aoidi, R., Llorian, M., Gibbins, D., Buechsenschuetz, C. L., Bussi, C., Flynn, H. R., Gilmore, T., Watson-Scales, S., Hansen, M. H., et al. (2024) · Science Translational Medicine · doi:10.1126/scitranslmed.add6883 · Cited by 46 · see citing works
Brault, V., Nguyen, T. L., Gutiérrez, J. F., Iacono, G. L., Birling, M., Lalanne, V., Méziane, H., Manousopoulou, A., Pavlovic, G., Lindner, L., et al. (2021) · PLoS Genetics · doi:10.1371/journal.pgen.1009777 · Cited by 41 · see citing works
Function and inhibition of DYRK1A: Emerging roles of treating multiple human diseases
Yang, Y., Fan, X., Liu, Y., Ye, D., Liu, C., Yang, H., Su, Z., Zhang, Y., & Liu, Y. (2023) · Biochemical Pharmacology · doi:10.1016/j.bcp.2023.115521 · Cited by 43 · see citing works
Willsey, H. R., Xu, Y., Everitt, A., Dea, J., Exner, C. R. T., Willsey, A. J., State, M. W., & Harland, R. M. (2020) · Development · doi:10.1242/dev.189290 · Cited by 42 · see citing works
Jhaisha, S. A., Widowati, E. W., Kii, I., Sonamoto, R., Knapp, S., Papadopoulos, C., & Becker, W. B. (2017) · Scientific Reports · doi:10.1038/s41598-017-06874-w · Cited by 41 · see citing works
Self-citationPotential Role of Microtubule Stabilizing Agents in Neurodevelopmental Disorders
Bonini, S. A., Mastinu, A., Ferrari‐Toninelli, G., & Memo, M. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18081627 · Cited by 40 · see citing works
“Indeed, DYRK1A overexpression causes a reduction in dendritic spine formation of cultured hippocampal neurons [126].”
BackgroundInfluentialLiao, A., Shi, R., Jiang, Y., Tian, S., Li, P., Song, F., Qu, Y., Li, J., Yun, H., & Yang, X. (2014) · Molecular Neurobiology · doi:10.1007/s12035-014-9006-0 · Cited by 40 · see citing works
RetractedResearch progress on therapeutic targeting of quiescent cancer cells
Zhang, J., Si, J., Gan, L., Di, C., Xie, Y., Sun, C., Li, H., Guo, M., & Zhang, H. (2019) · Artificial Cells Nanomedicine and Biotechnology · doi:10.1080/21691401.2019.1638793 · Cited by 40 · see citing works
“DYRK1A SH-SY5Y cell line (neuroblastoma) DYRK1A activates dormancy by 1) phosphorylating p27 and increasing its stability, 2) phosphorylating and degrading Cyclin D1, and 3) phosphorylating LIN52 to suppress cell cycle-dependent gene expression [33]”
Backgroundvan der Laden, J., Soppa, U., & Becker, W. B. (2015) · Cell Communication and Signaling · doi:10.1186/s12964-014-0082-6 · Cited by 39 · see citing works
“Furthermore, our observation that all HIPKs phosphorylate CDK inhibitor p27 on Ser10 highlights the similarity of target recognition by HIPKs with DYRK1A and DYRK1B [43].”
BackgroundSelf-citationUnderstanding the Multifaceted Role of Human Down Syndrome Kinase DYRK1A
Kay, L. J., Smulders-Srinivasan, T. K., & Soundararajan, M. (2016) · Advances in protein chemistry and structural biology · doi:10.1016/bs.apcsb.2016.07.001 · Cited by 38 · see citing works
Modeling Down syndrome in animals from the early stage to the 4.0 models and next
Moreno, M. D. M. M., Brault, V., Birling, M., Pavlovic, G., & Hérault, Y. (2020) · Progress in brain research · doi:10.1016/bs.pbr.2019.08.001 · Cited by 32 · see citing works
“DYRK1A impacts cell proliferation via the regulation of some cell cycle proteins like cyclinD1, p21Kip1 and p53 (Park et al., 2010, Najas et al., 2015, Soppa et al., 2014), promoting cell cycle exit (Hämmerle et al., 2011).”
BackgroundDisrupting the DREAM complex enables proliferation of adult human pancreatic β cells
Wang, P., Karaköse, E., Argmann, C., Wang, H., Balev, M., Brody, R., Rivas, H. G., Liu, X., Wood, O., Liu, H., et al. (2022) · Journal of Clinical Investigation · doi:10.1172/jci157086 · Cited by 35 · see citing works
“Also, several authors have indicated that DYR-K1A can phosphorylate, and thereby destabilize D-cyclins (60, 61), events that also would favor cell cycle arrest.”
Consequences of chromosome gain: A new view on trisomy syndromes
Krivega, M., Stiefel, C. M., & Štorchová, Z. (2022) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2022.10.014 · Cited by 40 · see citing works
p27Kip1, an Intrinsically Unstructured Protein with Scaffold Properties
Bencivenga, D., Stampone, E., Roberti, D., Ragione, F. D., & Borriello, A. (2021) · Cells · doi:10.3390/cells10092254 · Cited by 37 · see citing works
“During neurogenesis, cell cycle exit, cell migration and neuronal differentiation must be harmonized and, apparently, they are linked by p27 activities played in proliferation control [76,77], MTs’ dynamic regulation [78] and stabilization of Neurogenin 2 [79].”
BackgroundStagni, F., & Bartesaghi, R. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.903729 · Cited by 31 · see citing works
Kawatani, K., Nambara, T., Nawa, N., Yoshimatsu, H., Kusakabe, H., Hirata, K., Tanave, A., Sumiyama, K., Banno, K., Taniguchi, H., et al. (2021) · Communications Biology · doi:10.1038/s42003-021-02242-7 · Cited by 34 · see citing works
Cellular senescence and premature aging in Down Syndrome
Peng, L., Baradar, A. A., Aguado, J., & Wolvetang, E. J. (2023) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2023.111824 · Cited by 34 · see citing works
AlNajjar, Y. T., Gabr, M. T., ElHady, A. K., Salah, M., Wilms, G., Abadi, A., Becker, W. B., Abdel‐Halim, M., & Engel, M. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.113911 · Cited by 33 · see citing works
Self-citationMassey, A. J., Benwell, K. R., Burbridge, M. F., Kotschy, A., & Walmsley, L. (2021) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.17002 · Cited by 33 · see citing works
microRNA 155 up regulation in the CNS is strongly correlated to Down's syndrome dementia
Tili, E., Mezache, L., Michaille, J., Amann, V., Williams, J. M., Vandiver, P., Quiñónez, M., Fadda, P., Mikhail, A. A., & Nuovo, G. J. (2018) · Annals of Diagnostic Pathology · doi:10.1016/j.anndiagpath.2018.03.006 · Cited by 33 · see citing works
DYRK1A regulates Hap1–Dcaf7/WDR68 binding with implication for delayed growth in Down syndrome
Xiang, J., Yang, S., Xin, N., Gaertig, M. A., Reeves, R. H., Li, S., & Li, X.-J. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1614893114 · Cited by 32 · see citing works
“It has been reported that increased DYRK1A can affect cell-cycle regulation and neuronal differentiation by reducing cyclin D1 and the cyclindependent kinase inhibitor p21 (49, 50), two important proteins that promote neuronal differentiation (50–54).”
BackgroundAshford, A. L., Dunkley, T. P. J., Cockerill, M. J., Rowlinson, R. A., Baak, L., Gallo, R., Balmanno, K., Goodwin, L., Ward, R. A., Lochhead, P. A., et al. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-2032-x · Cited by 32 · see citing works
“DYRK1A and DYRK1B have also emerged as regulators of the cell cycle; both can promote the turnover of CCND1, increase expression of p21 and/or p27 and thereby promote cell cycle arrest and differentiation [22, 24, 25, 45, 55].”
BackgroundNew insights into the roles for DYRK family in mammalian development and congenital diseases
Yoshida, S., & Yoshida, K. (2022) · Genes & Diseases · doi:10.1016/j.gendis.2021.12.004 · Cited by 31 · see citing works
“Conversely, inhibition of Dyrk1A induces proliferation through a decrease in p27.(32,71) Other DYRK1A downstream molecules that contribute to neurogenesis include NOTCH, REST1, STAT, and WNT.”
BackgroundAristolactam BIII, a naturally derived DYRK1A inhibitor, rescues Down syndrome-related phenotypes
Choi, M., Kim, A., Ham, Y., Lee, J., Kim, D., Yang, A., Jo, M. J., Yoon, E., Heo, J., Han, S., et al. (2021) · Phytomedicine · doi:10.1016/j.phymed.2021.153695 · Cited by 31 · see citing works
Zhang, D., Wang, H., Liu, H., Tao, T., Wang, N., & Shen, A. (2015) · Molecular Neurobiology · doi:10.1007/s12035-015-9545-z · Cited by 31 · see citing works
DYRK1A promotes viral entry of highly pathogenic human coronaviruses in a kinase-independent manner
Strine, M. S., Cai, W. L., Wei, J., Alfajaro, M. M., Filler, R. B., Biering, S. B., Sarnik, S. A., Chow, R. D.-W., Patil, A., Cervantes, K. S., et al. (2023) · PLoS Biology · doi:10.1371/journal.pbio.3002097 · Cited by 29 · see citing works
Inhibition of DYRK1A disrupts neural lineage specificationin human pluripotent stem cells
Bellmaine, S. F., Ovchinnikov, D. A., Manallack, D. T., Cuddy, C., Elefanty, A. G., Stanley, E. G., Wolvetang, E. J., Williams, S. J., & Pera, M. F. (2017) · eLife · doi:10.7554/elife.24502 · Cited by 30 · see citing works
“In several model systems, DYRK1A overexpression led to exit of neural stem cells from the cell cycle, through mechanisms involving cyclin D1 and p53 (Najas et al., 2015; Park et al., 2010; Soppa et al., 2014; Yabut et al., 2010).”
BackgroundDYRK1A Negatively Regulates CDK5-SOX2 Pathway and Self-Renewal of Glioblastoma Stem Cells
Chen, B., McCuaig-Walton, D., Tan, S. J. X., Montgomery, A. P., Day, B. W., Kassiou, M., Munoz, L., & Recasens, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22084011 · Cited by 30 · see citing works
“This is most likely through the ability of DYRK1A to mark various proteins for proteosomal degradation [31–33] and aligns with previous studies reporting DYRK1A-regulated degradation of cyclin B and cyclin D [13,14,17].”
BackgroundRedhead, Y. T., Gibbins, D., Lana‐Elola, E., Watson-Scales, S., Dobson, L., Krause, M., Liu, K. J., Fisher, E., Green, J. B. A., & Tybulewicz, V. L. J. (2023) · Development · doi:10.1242/dev.201077 · Cited by 29 · see citing works
Shared Etiology in Autism Spectrum Disorder and Epilepsy with Functional Disability
Zahra, A., Wang, Y., Wang, Q., & Wu, J. (2022) · Behavioural Neurology · doi:10.1155/2022/5893519 · Cited by 30 · see citing works
“In mouse models, Dyrk1A has been shown to perform critical roles in cell cycle regulation and synaptic plasticity [116].”
BackgroundMurtaza, N., Uy, J. A., & Singh, K. K. (2020) · Molecular Autism · doi:10.1186/s13229-020-00334-5 · Cited by 29 · see citing works
“Cytosolic DYRK1A was originally associated with cell cycle and cytoskeleton organization [69, 70], but a novel function for DNA damage repair was shown in the nuclear compartment [71].”
BackgroundThe Temporal Regulation of S Phase Proteins During G1
Grant, G. D., & Cook, J. G. (2017) · Advances in experimental medicine and biology · doi:10.1007/978-981-10-6955-0_16 · Cited by 26 · see citing works
“In G0, Lin52 Ser28 is phosphorylated by DYRK1A kinase, a protein kinase with multiple roles in cell proliferation and neuronal development (Chen et al. 2013; Soppa et al. 2014).”
BackgroundGao, M., Zhang, T., Chen, T., Chen, Z., Zhu, Z., Wen, Y., Qin, S., Bao, Y., Zhao, T., Li, H., et al. (2024) · Theranostics · doi:10.7150/thno.89878 · Cited by 25 · see citing works
“In GCs, SMAD3 in the cytoplasm is phosphorylated to p-SMAD3 by GDF9 signals and transferred to the nucleus to regulate proliferation [48, 49].”
BackgroundLaham, A. J., El‐Awady, R., Saber-Ayad, M. M., Wang, N., Yan, G., Boudreault, J., Ali, S., & Lebrun, J. J. (2024) · npj Precision Oncology · doi:10.1038/s41698-024-00614-w · Cited by 24 · see citing works
“DYRK1Aregulates cell cycleand differentiation of neuronal cells by inducing G0/G1 arrest through phosphorylation and subsequent degradation of cyclin D as well as through stabilization of the cyclin-dependent kinase inhibitor p27 Kip protein 7 .”
Insights from the protein interaction Universe of the multifunctional “Goldilocks” kinase DYRK1A
Ananthapadmanabhan, V., Shows, K. H., DICKINSON, A. J. G., & Litovchick, L. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1277537 · Cited by 23 · see citing works
Yan, Y., Zhao, J., Cao, C., Jia, Z., Zhou, N., Han, S., Wang, Y., Xu, Y., Zhao, J., Yan, Y., et al. (2014) · Neuroscience · doi:10.1016/j.neuroscience.2014.08.010 · Cited by 23 · see citing works
Chen, W., Zhong, X. Y., Wei, Y., Liu, Y., Quan, Y., Zhang, G., He, L., Chen, F., Liu, Y., & Luo, J. (2015) · Molecular Neurobiology · doi:10.1007/s12035-015-9121-6 · Cited by 21 · see citing works
“Cyclin D1 expression is regulated by mitogenic signaling through the Rassignaling pathway involving Ras/Raf/mitogen-activated protein [23].”
BackgroundRetractedCurrent Analysis of Skeletal Phenotypes in Down Syndrome
Thomas, J. R., & Roper, R. J. (2021) · Current Osteoporosis Reports · doi:10.1007/s11914-021-00674-y · Cited by 21 · see citing works
The Tumor Suppressor NKX3.1 Is Targeted for Degradation by DYRK1B Kinase
Song, L., Silva, J., Koller, A. A., Rosenthal, A. S., Chen, E. I., & Gelmann, E. P. (2015) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-14-0680 · Cited by 21 · see citing works
“In vitro kinase assay was performed according to the assay conditions reported previously (19, 20).”
MethodNurunnabi, S. M., Gutiérrez-Aviñó, F. J., Colonques, J., Cerón, J., Hämmerle, B., & Tejedor, F. J. (2016) · Development · doi:10.1242/dev.134338 · Cited by 20 · see citing works
“Intriguingly, the vertebrate Mnb/Dyrk1A orthologs (Yabut et al., 2010; Litovchick et al., 2011; Hämmerle et al., 2011; Soppa et al., 2014) and other DYRKs (reviewed by Becker, 2012) appear to act as cell cycle repressors in both neural and non-neural mammalian cells.”
BackgroundSelf-citationLiu, Q., Tang, Y., Chen, L., Liu, N., Lang, F., Liu, H., Wang, P., & Sun, X.-L. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.717553 · Cited by 18 · see citing works
“Our study and the recent studies from others proposed that proliferative repression caused by DYRK1A overexpression could be due to cell cycle arrest at G0/G1 phase (14, 31, 43, 44).”
BackgroundDown syndrome mouse models have an abnormal enteric nervous system
Schill, E. M., Wright, C. M., Jamil, A., LaCombe, J., Roper, R. J., & Heuckeroth, R. O. (2019) · JCI Insight · doi:10.1172/jci.insight.124510 · Cited by 19 · see citing works
Coskun, P. E., Helguera, P. R., Nemati, Z., Bohannan, R. C., Thomas, J., Samuel, S. E., Argueta, J., Doran, E. W., Wallace, D. C., Lott, I. T., et al. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-160278 · Cited by 19 · see citing works
DCAF7/WDR68 is required for normal levels of DYRK1A and DYRK1B
Yousefelahiyeh, M., Xu, J., Alvarado, E., Yang, Y., Salven, D. S., & Nissen, R. M. (2018) · PLoS ONE · doi:10.1371/journal.pone.0207779 · Cited by 19 · see citing works
Wang, P., Wang, L., Chen, L., & Sun, X. (2017) · Scientific Reports · doi:10.1038/s41598-017-07655-1 · Cited by 18 · see citing works
Salah, M., Abdel‐Halim, M., & Engel, M. (2018) · MedChemComm · doi:10.1039/c8md00142a · Cited by 18 · see citing works
Cell models for Down syndrome-Alzheimer’s disease research
Wu, Y., West, N. R., Bhattacharyya, A., & Wiseman, F. K. (2022) · Neuronal Signaling · doi:10.1042/ns20210054 · Cited by 17 · see citing works
Hogg, E. K. J., & Findlay, G. M. (2023) · FEBS Letters · doi:10.1002/1873-3468.14723 · Cited by 16 · see citing works
“DYRK1A may also promote neuronal differentiation by inducing G0/G1 arrest via phosphorylation of Cyclin D1 and p27(kip1) [127], and regulate neuronal maturation by promoting ubiquitin-mediated degradation of the REST transcriptional regulator [210,218,220,275].”
BackgroundMuscle stem cell dysfunction impairs muscle regeneration in a mouse model of Down syndrome
Pawlikowski, B. T., Betta, N. D., Elston, T. L., Williams, D. A., & Olwin, B. B. (2018) · Scientific Reports · doi:10.1038/s41598-018-22342-5 · Cited by 17 · see citing works
Recent research and development of DYRK1A inhibitors
Zhao, L., Xiong, X., Liu, L., Liang, Q., Tong, R., Feng, X., Bai, L., & Shi, J. (2021) · Chinese Chemical Letters · doi:10.1016/j.cclet.2021.10.003 · Cited by 16 · see citing works
DYRK1A-mediated PLK2 phosphorylation regulates the proliferation and invasion of glioblastoma cells
Tan, S., Zhao, J., & Wang, P. (2023) · International Journal of Oncology · doi:10.3892/ijo.2023.5542 · Cited by 16 · see citing works
“…a tumor-promoting role in acute megakaryocytic leukemia in Down's syndrome models (42), B-cell acute lymphoblastic leukemia (14), neuro-blastoma (43), pancreatic ductal adenocarcinoma (44), ovarian cancer (45), non-small cell lung cancer (46,47), bladder cancer (48) and head and neck squamous…”
Gehlot, P., Pathak, R., Kumar, S., Choudhary, N. K., & Vyas, V. K. (2024) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2024.117925 · Cited by 16 · see citing works
Synergistic roles of DYRK1A and GATA1 in trisomy 21 megakaryopoiesis
Sit, Y. T., Takasaki, K., An, H. H., Xiao, Y., Hurtz, C., Gearhart, P. A., Zhang, Z., Gadue, P. J., French, D. L., & Chou, S. T. (2023) · JCI Insight · doi:10.1172/jci.insight.172851 · Cited by 15 · see citing works
Wan, X., Wang, W., & Liang, Z. (2021) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-021-04154-w · Cited by 15 · see citing works
“Among the potential targets to intervene with this disease, DYRK1A, which is ubiquitously expressed during early brain development, emerged as a promising therapeutic candidate for unmet clinical needs [1].”
BackgroundKokkorakis, N., & Gaitanou, M. (2020) · World Journal of Stem Cells · doi:10.4252/wjsc.v12.i12.1553 · Cited by 16 · see citing works
Structure-activity relationship for the folding intermediate-selective inhibition of DYRK1A
Miyazaki, Y., Kikuchi, M., Umezawa, K., Descamps, A., Nakamura, D., Furuie, G., Sumida, T., Saito, K., Kimura, N., Niwa, T., et al. (2022) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.113948 · Cited by 14 · see citing works
Regeneration of Pancreatic β-Cells for Diabetes Therapeutics by Natural DYRK1A Inhibitors
Guo, Y., Li, L., Yao, Y., & Li, H. (2022) · Metabolites · doi:10.3390/metabo13010051 · Cited by 14 · see citing works
“DYRK1A phosphorylates cyclin D1 at Thr286 in the S phase of the cells, promoting cyclin D1 to leave the nucleus and be degraded by the proteasome [49].”
BackgroundHe, M., Gu, J., Zhu, J., Wang, X., Wang, C., Duan, C., Ni, Y., Lü, X., & Li, J. (2018) · Neuropeptides · doi:10.1016/j.npep.2018.04.008 · Cited by 14 · see citing works
- Authors
- Soppa, U., Schumacher, J., Florencio Ortiz, V., Pasqualon, T., Tejedor, F., & Becker, W.
- Affiliations
- Universitat de Miguel Hernández d'Elx (ES)
- RWTH Aachen University (DE)
- Corresponding author
- Becker, Walter
- Venue
- Cell Cycle
- Publisher
- Informa UK Limited
- Published
- 2014-05-07
- Volume
- 13
- Issue
- 13
- Pages
- 2084-2100
- ISSN
- 1538-4101 (ISSN-L)
- 1551-4005
- PMC
- PMC4111700
- OpenAlex
- W2015658471
- Cited by
- 189
- References
- 80
- Citations by year
- 2026: 20 · 2025: 10 · 2024: 16 · 2023: 19 · 2022: 15 · 2021: 22 · 2020: 11 · 2019: 12 · 2018: 10 · 2017: 17 · 2016: 18 · 2015: 17 · 2014: 2
- FWCI
- 6.26
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Cell Cycle (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- RWTH Publications (RWTH Aachen) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- DYRK1A, Down syndrome, p27, cyclin D1, protein phosphorylation, cell cycle exit, neuronal differentiation, neurogenesis, G1 cell cycle arrest, protein stability, proteasomal degradation, SH-SY5Y cells, hippocampal neurons, kinase activity
- MeSH terms
- Dyrk Kinases, Animals, Brain, Cell Cycle, Cell Differentiation, Cell Line, Down Syndrome, Humans, Mice, Inbred ICR, Neurons, Phosphorylation, Protein-Tyrosine Kinases, Serine, Threonine, Protein Serine-Threonine Kinases, Cyclin D1, Cyclin-Dependent Kinase Inhibitor p27, Neurogenesis, Primary Cell Culture
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