DYRK1A enhances the mitogen-activated protein kinase cascade in PC12 cells by forming a complex with Ras, B-Raf, and MEK1.
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.
Kelly
Paul A
PA
Institut National de la Santé et de la Recherche Médicale U584, Faculté de Médecine Necker-Enfants Malades, 75730 Paris Cedex 15, France.
Rahmani
Zohra
Z
D000818:Animals; D002454:Cell Differentiation; D004314:Down Syndrome; D015536:Down-Regulation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D020932:Nerve Growth Factor / Q000494:pharmacology; D016501:Neurites / Q000502:physiology; D016716:PC12 Cells; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism*; D051381:Rats; D015533:Transcriptional Activation; D015854:Up-Regulation; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism*; D000097603:Dyrk Kinases
D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; D020932:Nerve Growth Factor; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D048493:Proto-Oncogene Proteins B-raf; D050807:ets-Domain Protein Elk-1; D018631:ras Proteins; D000097603:Dyrk Kinases; C494114:Elk1 protein, rat