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Cited by 86Protein Kinase Regulation and GTPase SignalingProtein Tyrosine PhosphatasesMelanoma and MAPK Pathways

DYRK1A enhances the mitogen-activated protein kinase cascade in PC12 cells by forming a complex with Ras, B-Raf, and MEK1

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Kelly, Paul A., Rahmani, Zohra·2005·Molecular Biology of the Cell
DOI 10.1091/mbc.e04-12-1085PMC PMC1182298
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Abstract

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.

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  • Expression of MNB/DYRK1A or Dyrk1a induces neuronal differentiation in neural cell lines.

    “Expression of MNB/DYRK1A or Dyrk1a induces neuronal differentiation in neural cell lines (Kelly and Rahmani, 2005; Yang et al., 2001)”

    From Sex-specific developmental alterations in DYRK1A expression in the brain of a Down syndrome mouse model (2024) · cites this paper as Kelly and Rahmani, 2005

    The Results and Discussion report that DYRK1A expression enhances neuronal differentiation in PC12 cells, including neurite outgrowth and neuronal marker expression. The experiments involved NGF treatment, however, so this paper supports potentiation of NGF-mediated differentiation, not that DYRK1A expression alone induces it. (LLM, conf=0.87)

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  1. Altafaj, X., et al. (2001). Neurodevelopmental delay, motor abnormalities and cognitive deficits in transgenic mice overexpressing Dyrk1A (minibrain), a murine model of Down's syndrome. Hum. Mol. Genet. 10, 1915–1923. [DOI] [PubMed] [Google Scholar]
  2. Bahler, J., and Pringle, J. R. (1998). Pom1p, a fission yeast protein kinase that provides positional information for both polarized growth and cytokinesis. Genes Dev. 12, 1356–1370. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Becker, L., Mito, T., Yakashima, S., and Onodera, K. (1991). Growth and development of the brain in Down syndrome. In: The Morphogenesis of Down Syndrome, New York: Wiley-Liss, 133–152. [PubMed]
  4. Becker, W., and Joost, H. G. (1999). Structural and functional characteristics of Dyrk, a novel subfamily of protein kinases with dual specificity. Prog. Nucleic Acids Res. Mol. Biol. 62, 1–17. [DOI] [PubMed] [Google Scholar]
  5. Becker, W., Weber, Y., Wetzel, K., Eirmbter, K., Tejedor, F. J., and Joost, H. G. (1998). Sequence characteristics, subcellular localization, and substrate specificity of DYRK-related kinases, a novel family of dual specificity protein kinases. J. Biol. Chem. 273, 25893–25902. [DOI] [PubMed] [Google Scholar]
  6. Catling, A. D., Schaeffer, H.-J., Reuter, C.W.M., Reddy, G. R., and Weber, M. J. (1995). A proline-rich sequence unique to MEK1 and MEK2 is required for Raf binding and regulates MEK function. Mol. Cell. Biol. 15, 5214–5225. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chen-Hwang, M. C., Chen, H. R., Elzinga, M., and Hwang, Y. W. (2002). Dynamin is a minibrain kinase/dual specificity Yak1-related kinase 1A substrate. J. Biol. Chem. 277, 17597–17604. [DOI] [PubMed] [Google Scholar]
  8. Coyle, J. T., Oster-Granite, M. L., and Gearhart, J. D. (1986). The neurobiologic consequences of Down syndrome. Brain Res. Bull. 16, 773–787. [DOI] [PubMed] [Google Scholar]
  9. Delabar, J. M., Theophile, D., Rahmani, Z., Chettouh, Z., Blouin, J. L., Prieur, M., Noel, B., and Sinet, P. M. (1993). Molecular mapping of twenty-four features of Down syndrome on chromosome 21. Eur. J. Hum. Genet. 1, 114–124. [DOI] [PubMed] [Google Scholar]
  10. Epstein, C. J. (2000). Down syndrome (trisomy 21). In: The Metabolic and Molecular Bases of Inherited Disease, ed. C. R. Scriver and W. S. Sly, New York: McGraw-Hill Book Co., 1223–1256
  11. Feig, L. A., and Cooper, G. M. (1988). Inhibition of NIH 3T3 cell proliferation by a mutant ras protein with preferential affinity for GDP. Mol. Cell. Biol. 8, 3235–3243. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fotaki, V., Dierssen, M., Alcantara, S., Martinez, S., Marti, E., Casas, C., Visa, J., Soriano, E., Estivill, X., and Arbones, M. L. (2002). Dyrk1A haploinsufficiency affects viability and causes developmental delay and abnormal brain morphology in mice. Mol. Cell. Biol. 22, 6636–6647. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Galceran, J., De Graaf, K., Tejedor, F. J., and Becker, W. (2003). The MNB/DYRK1A protein kinase: genetic and biochemical properties. J. Neural Transm. Suppl. 67, 139–148. [DOI] [PubMed] [Google Scholar]
  14. Garrett, S., and Broach, J. (1989). Loss of Ras activity in saccharomyces cerevisiae is suppressed by disruptions of a new kinase gene, YAKI, whose product may act downstream of the cAMP-dependent protein kinase. Genes Dev. 3, 1336–1348. [DOI] [PubMed] [Google Scholar]
  15. Greene, L. A., and Tischler, A. S. (1976). Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Proc. Natl. Acad. Sci. USA 73, 2424–2428. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Guimera, J., Casas, C., Estivill, X., and Pritchard, M. (1999). Human minibrain homologue (MNBH/DYRK1): characterization, alternative splicing, differential tissue expression, and overexpression in Down syndrome. Genomics 57, 407–418. [DOI] [PubMed] [Google Scholar]
  17. Guimera, J., Casas, C., Pucharcos, C., Solans, A., Domenech, A., Planas, A. M., Ashley, J., Lovett, M., Estivill, X., and Pritchard, M. A. (1996). A human homologue of Drosophila minibrain (MNB) is expressed in the neuronal regions affected in Down syndrome and maps to the critical region. Hum. Mol. Genet. 5, 1305–1310. [DOI] [PubMed] [Google Scholar]
  18. Hämmerle, B., Carnicero, A., Elizalde, C., Ceron, J., Martinez, S., and Tejedor, F. J. (2003a). Expression patterns and subcellular localization of the Down syndrome candidate protein MNB/DYRK1A suggest a role in late neuronal differentiation. Eur. J. Neurosci. 17, 2277–2286. [DOI] [PubMed] [Google Scholar]
  19. Hämmerle, B., Elizalde, C., Galceran, J., Becker, W., and Tejedor, F. J. (2003b). The MNB/DYRK1A protein kinase: neurobiological functions and Down syndrome implications. J. Neural Transm. Suppl. 67, 129–137. [DOI] [PubMed] [Google Scholar]
  20. Himpel, S., Tegge, W., Frank, R., Leder, S., Joost, H. G., and Becker, W. (2000). Specificity determinants of substrate recognition by the protein kinase DYRK1A. J. Biol. Chem. 275, 2431–2438. [DOI] [PubMed] [Google Scholar]
  21. Kentrup, H., Becker, W., Heukelbach, J., Wilmes, A., Schrmann, A., Huppertz, C., Kainulainen, H., and Joost, H. G. (1996). Dyrk, a dual specificity protein kinase with unique structural features. whose activity is dependent on tyrosine residues between subdomains VII and VIII. J. Biol. Chem. 271, 3488–3495. [DOI] [PubMed] [Google Scholar]
  22. Kim, D., et al. (2004). Regulation of Dyrk1A kinase activity by 14–3-3. Biochem. Biophys. Res. Commun. 323, 499–504. [DOI] [PubMed] [Google Scholar]
  23. Kolch, W. (2000). Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions. Biochem. J. 351, 289–305. [PMC free article] [PubMed] [Google Scholar]
  24. Li, W., Han, M., and Guan; K.-L. (2000). The leucine-rich repeat protein SUR-8 enhances MAPK kinase activation and forms a complex with Ras and Raf. Genes Dev. 14, 895–900. [PMC free article] [PubMed] [Google Scholar]
  25. Mao, J., Maye, P., Kogerman, P., Tejedor, F. J., Toftgard, R., Xie, W., Wu, G., and Wu, D. (2002). Regulation of Gli1 transcriptional activity in the nucleus by Dyrk1. J. Biol. Chem. 277, 35156–35161. [DOI] [PubMed] [Google Scholar]
  26. Mao, R., Zielke, C. L., Zielke, H. R., and Pevsner, J. (2003). Global up-regulation of chromosome 21 gene expression in the developing Down syndrome brain. Genomics 81, 457–467. [DOI] [PubMed] [Google Scholar]
  27. Marti, E., Altafaj, X., Dierssen, M., de la Luna, S., Fotaki, V., Alvarez, M., Perez-Riba, M., Ferrer, I., and Estivill, X. (2003). Dyrk1A expression pattern supports specific roles of this kinase in the adult central nervous system. Brain Res. 964, 250–263. [DOI] [PubMed] [Google Scholar]
  28. Matsuo, R., Ochiai, W., Nakashima, K., and Taga, T. (2001). A new expression cloning strategy for isolation of substrate-specific kinases by using phosphorylation site-specific antibody. J. Immunol. Methods 247, 141–151. [DOI] [PubMed] [Google Scholar]
  29. Moodie, S. A., Willumsen, B. M., Weber, M. J., and Wolfman, A. (1993). Complexes of Ras/GTP with Raf-1 and mitogen-activated protein kinase kinase. Science 260, 1658–1661. [DOI] [PubMed] [Google Scholar]
  30. Muller, J., Cacace, A. M., Lyons, W. E., Mc Gill, C. B., and Morrison, D. K. (2000). Identification of B-KSR1, a novel brain specific isoform of KSR1 that functions in neuronal signalling. Mol. Cell. Biol. 20, 5529–5539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Nadel, L. (2003). Down's syndrome: a genetic disorder in biobehavioral perspective. Genes Brain Behav. 2, 156–166. [DOI] [PubMed] [Google Scholar]
  32. Papin, C., Denouel, A., Calothy, G., and Eychène, A. (1996). Identification of signalling proteins interacting with B-Raf in the yeast two-hybrid system. Oncogene 12, 2213–2221. [PubMed] [Google Scholar]
  33. Qui, M. S., and Green, S. H. (1992). PC12 cell neuronal differentiation is associated with prolonged p21ras activity and consequent prolonged ERK activity. Neuron 9, 705–717. [DOI] [PubMed] [Google Scholar]
  34. Rahmani, Z., Blouin, J. L., Creau-Goldberg, N., Watkins, P. C., Mattei, J. F., Poissonnier, M., Prieur, M., Chettouh, Z., Nicole, A., and Aurias, A. (1989). Critical role of the D21S55 region on chromosome 21 in the pathogenesis of Down syndrome. Proc. Natl. Acad. Sci. USA 86, 5958–5962. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Rahmani, Z., Blouin, J. L., Creau-Goldberg, N., Watkins, P. C., Mattei, J. F., Poissonnier, M., Prieur, M., Chettouh, Z., Nicole, A., and Aurias, A. (1990). Down syndrome critical region around D21S55 on proximal 21q22.3. Am. J. Med. Gene Suppl. 7, 98–103. [DOI] [PubMed] [Google Scholar]
  36. Rahmani, Z., Lopes, C., Rachidi, M., and Delabar, J. M. (1998). Expression of the mnb (dyrk) protein in adult and embryonic mouse tissues. Biochem. Biophys. Res. Commun. 253, 514–518. [DOI] [PubMed] [Google Scholar]
  37. Raich, W. B., Moorman, C., Lacefield, C. O., Lehrer, J., Bartsch, D., Plasterk, R.H.A., Kandel, E. R., and Hobert, O. (2003). Characterization of Caenorhabditis elegans homologs of the Down syndrome candidate gene DYRK1A. Genetics 163, 571–580. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Raz, N., Torres, I. J., Briggs, S. D., Spencer, W. D., Thornton, A. E., Loken, W. J., Gunning, F. M., McQuain, J. D., Driesen, N. R., and Acker, J. D. (1995). Selective neuroanatomic abnormalities in Down's syndrome and their cognitive correlates: evidence from MRI morphometry. Neurology 45, 356–366. [DOI] [PubMed] [Google Scholar]
  39. Robinson, M. J., and Cobb, M. H. (1997). Mitogen-activated protein kinase pathways. Curr. Opin. Cell Biol. 9, 180–186. [DOI] [PubMed] [Google Scholar]
  40. Shindoh, N., Kudoh, J., Maeda, H., Yamaki, A., Minoshima, S., Shimizu, Y., and Shimizu, N. (1996). Cloning of a human homolog of the Drosophila minibrain/rat Dyrk gene from the Down syndrome critical region of chromosome 21. Biochem. Biophys. Res. Commun. 225, 92–99. [DOI] [PubMed] [Google Scholar]
  41. Sitz, J. H., Tigges, M., Baumgärtel, K., Khaspekov, L. G., and Lutz, B. (2004). Dyrk1A potentiates steroid hormone-induced transcription via the chromatin remodeling factor Arip4. Mol. Cell. Biol. 24, 5821–5834. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Skurat, A. V., and Dietrich, A. D. (2004). Phosphorylation of Ser640 in muscle glycogen synthase by DYRK family protein kinases. J. Biol. Chem. 279, 2490–2498. [DOI] [PubMed] [Google Scholar]
  43. Smith, D. J., and Rubin, E. M. (1997). Functional screening and complex traits: human 21q22.2 sequences affecting learning in mice. Hum. Mol. Genet. 6, 1729–1733. [DOI] [PubMed] [Google Scholar]
  44. Smith, D. J., et al. (1997). Functional screening of 2 Mb of human chromosome 21q22.2 in transgenic mice implicates minibrain in learning defects associated with Down syndrome. Nat. Genet. 16, 28–36. [DOI] [PubMed] [Google Scholar]
  45. Song, W. J., Chung, S. H., and Kurnit, D. M. (1997). The murine Dyrk protein maps to chromosome 16, localizes to the nucleus, and can form multimers. Biochem. Biophys. Res. Commun. 231, 640–644. [DOI] [PubMed] [Google Scholar]
  46. Song, W. J., et al. (1996). Isolation of human and murine homologues of the Drosophila minibrain gene: human homologue maps to 21q22.2 in the Down syndrome “critical region.” Genomics 38, 331–339. [DOI] [PubMed] [Google Scholar]
  47. Stewart, S., and Guan, K. L. (2000). The dominant negative Ras mutant, N17Ras, can inhibit signalling independently of blocking Ras activation. J. Biol. Chem. 275, 8854–8862. [DOI] [PubMed] [Google Scholar]
  48. Sugimoto, T., Stewart, S., Han, M., and Guan, K.-L. (1997). The kinase suppressor of Ras (KSR) modulates growth factor and Ras signaling by uncoupling elk-1 phosphorylation from MAP kinase activation. EMBO J. 17, 1717–1727. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Tejedor, F., Zhu, X. R., Kaltenbach, E., Ackermann, A., Baumann, A., Canal, I., Heisenberg, M., Fischbach, K. F., and Pongs, O. (1995). Ninibrain: a new protein kinase family involved in postembryonic neurogenesis in Drosophila. Neuron 14, 287–301. [DOI] [PubMed] [Google Scholar]
  50. Van Es, S., Weening, K. E., and Devreotes, P. N. (2001). The protein YakA regulates g-protein-linked signaling responses during growth and development of Dictyostelium. J. Biol. Chem. 276, 30761–30765. [DOI] [PubMed] [Google Scholar]
  51. Vicari, S., Bellucci, S., and Carlesimo, G. A. (2000). Implicit and explicit memory: a functional dissociation in persons with Down syndrome. Neuropsychologia 38, 240–251. [DOI] [PubMed] [Google Scholar]
  52. von Groote-Bidlingmaier, F., Schmoll, D., Orth, H. M., Joost, H. G., Becker, W., and Barthel, A. (2003). DYRK1 is a co-activator of FKHR (FOXO1a)-dependent glucose-6-phosphatase gene expression. Biochem. Biophys. Res. Commun. 300, 764–769. [DOI] [PubMed] [Google Scholar]
  53. Vossler, M. R., Yao, H., York, R. D., Pan, M. G., Rim, C. S., and Stork, P. J. (1997). cAMP activates MAP kinase and Elk-1 through a B-Raf- and Rap1-dependent pathway. Cell 89, 73–82. [DOI] [PubMed] [Google Scholar]
  54. Wittinghofer, A., and Nassar, N. (1996). How Ras-related proteins talk to their effectors. Trends Biochem. Sci. 21, 488–491. [DOI] [PubMed] [Google Scholar]
  55. Woods, Y. L., Cohen, P., Becker, W., Jakes, R., Goedert, M., Wang, X., and Proud, C. G. (2001a). The kinase DYRK phosphorylates protein-synthesis initiation factor eIF2Bepsilon at Ser539 and the microtubule-associated protein tau at Thr 212, potential role for DYRK as a glycogen synthase kinase 3-priming kinase. Biochem. J. 355, 609–615. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Woods, Y. L., Rena, G., Morrice, N., Barthel, A., Becker, W., Guo, S., Unterman, T. G., and Cohen, P. (2001b). The kinase DYRK1A phosphorylates the transcription factor FKHR at Ser329 in vitro, a novel in vivo phosphorylation site. Biochem. J. 355, 597–607. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Yang, E. J., Ahn, Y. S., and Chung, K. C. (2001). Protein kinase Dyrk1 activates cAMP response element-binding protein during neuronal differentiation in hippocampal progenitor cells. J. Biol. Chem. 276, 39819–39824. [DOI] [PubMed] [Google Scholar]

Cited by

Sorted by citations

Authors
Kelly, P. A., & Rahmani, Z.
Affiliations
Hôpital Necker-Enfants Malades (FR)
ORCID
Venue
Molecular Biology of the Cell
Publisher
American Society for Cell Biology (ASCB)
Published
2005-08
Volume
16
Issue
8
Pages
3562-3573
ISSN
  • 1059-1524 (ISSN-L)
  • 1939-4586
DOI
10.1091/mbc.e04-12-1085
PMC
PMC1182298
OpenAlex
W2114466755
Cited by
86
References
62
Citations by year
2026: 4 · 2025: 4 · 2024: 2 · 2023: 6 · 2022: 3 · 2021: 4 · 2020: 5 · 2019: 5 · 2018: 1 · 2017: 3 · 2016: 3 · 2015: 5 · 2014: 2 · 2013: 6 · 2012: 4
FWCI
1.76
Type
journal article
Language
en
Open access
Locations
  • Molecular Biology of the Cell (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • University of Michigan
  • University of Virginia
  • Institut National de la Santé et de la Recherche Médicale
  • Centre National de la Recherche Scientifique
  • Medical School, University of Michigan
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
Keywords
DYRK1A, RAS/MAPK pathway, BRAF, MEK1, ERK activation, nerve growth factor, neuronal differentiation, PC12 cells, Down syndrome, kinase-independent signaling, protein complex formation, minibrain
MeSH terms
Dyrk Kinases, Animals, Cell Differentiation, Down Syndrome, HeLa Cells, Humans, Protein Binding, Protein-Tyrosine Kinases, Transcriptional Activation, Down-Regulation, Up-Regulation, Neurites, PC12 Cells, Protein Serine-Threonine Kinases, ras Proteins, Nerve Growth Factor, MAP Kinase Signaling System, Extracellular Signal-Regulated MAP Kinases, MAP Kinase Kinase 1, Proto-Oncogene Proteins B-raf, ets-Domain Protein Elk-1, Rats

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