The Down syndrome candidate dual-specificity tyrosine phosphorylation-regulated kinase 1A phosphorylates the neurodegeneration-related septin 4
| Autor: | Jan Hendrik Sitz, Walter Becker, Chrisovalantis Papadopoulos, Beat Lutz, Francisco J. Tejedor, Karsten Baumgärtel, Paul Hekerman, Barbara Hämmerle |
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| Rok vydání: | 2008 |
| Předmět: |
DYRK1A
Green Fluorescent Proteins Protein Serine-Threonine Kinases Transfection MAP2K7 GTP Phosphohydrolases chemistry.chemical_compound Mice Two-Hybrid System Techniques medicine Animals Humans Immunoprecipitation ASK1 RNA Messenger Phosphorylation Protein kinase A Cell Line Transformed Neurons biology Cyclin-dependent kinase 4 General Neuroscience Neurodegeneration Brain Tyrosine phosphorylation Protein-Tyrosine Kinases medicine.disease Cytoskeletal Proteins Protein kinase domain Biochemistry chemistry Mutation biology.protein Septins |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| ISSN: | 0306-4522 |
| Popis: | The dual-specific kinase DYRK1A (dual-specificity tyrosine phosphorylation-regulated kinase 1A) is the mammalian orthologue of the Drosophila minibrain (MNB) protein kinase and executes diverse roles in neuronal development and adult brain physiology. DYRK1A is overexpressed in Down syndrome (DS) and has recently been implicated in several neurodegenerative diseases. In an attempt to elucidate the molecular basis of its involvement in cognitive and neurodegeneration processes, we searched for novel proteins interacting with the kinase domain of DYRK1A in the adult mouse brain and identified septin 4 (SEPT4, also known as Pnutl2/CDCrel-2). SEPT4 is a member of the group III septin family of guanosine triphosphate hydrolases (GTPases), which has previously been found in neurofibrillary tangles of Alzheimer disease brains and in α-synuclein-positive cytoplasmic inclusions in Parkinson disease brains. In transfected mammalian cells, DYRK1A specifically interacts with and phosphorylates SEPT4. Phosphorylation of SEPT4 by DYRK1A was inhibited by harmine, which has recently been identified as the most specific inhibitor of DYRK1A. In support of a physiological relation in the brain, we found that Dyrk1A and Sept4 are co-expressed and co-localized in neocortical neurons. These findings suggest that SEPT4 is a substrate of DYRK1A kinase and thus provide a possible link for the involvement of DYRK1A in neurodegenerative processes and in DS neuropathologies. © 2008 IBRO. This work was supported by a Boehringer Ingelheim Fonds PhD scholarship to J.H.S., a Deutsche Forschungsgemeinschaft (DFG) grant to W.B. (Be-1967/2–1) and Ministerio de Educacion y Ciencia (SAF2007-61722) grant to F.T., and DAAD Acciones Integradas grants to F.T. (HA2005-0133) and W.B. (No. D/05/25692). |
| Databáze: | OpenAIRE |
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