title: Phosphorylation of Munc18-1 by Dyrk1A regulates its interaction with Syntaxin 1 and X11α.
abstract: Dual-specificity tyrosine(Y)-phosphorylation-regulated kinase 1A (Dyrk1A) is a protein kinase that might be responsible for mental retardation and early onset of Alzheimer's disease in Down's syndrome patients. Dyrk1A plays a role in many cellular pathways through phosphorylation of diverse substrate proteins; however, its role in synaptic vesicle exocytosis is poorly understood. Munc18-1, a central regulator of neurotransmitter release, interacts with Syntaxin 1 and X11α. Syntaxin 1 is a key soluble N-ethylmaleimide-sensitive factor attachment protein receptor protein involved in synaptic vesicle docking/fusion events, and X11α modulates amyloid precursor protein processing and β amyloid generation. In this study, we demonstrate that Dyrk1A interacts with and phosphorylates Munc18-1 at the Thr(479) residue. The phosphorylation of Munc18-1 at Thr(479) by Dyrk1A stimulated binding of Munc18-1 to Syntaxin 1 and X11α. Furthermore, the levels of phospho-Thr(479) -Munc18-1 were enhanced in the brains of transgenic mice over-expressing Dyrk1A protein, providing in vivo evidence of Munc18-1 phosphorylation by Dyrk1A. These results reveal a link between Munc18-1 and Dyrk1A in synaptic vesicle trafficking and amyloid precursor protein processing, suggesting that up-regulated Dyrk1A in Down's syndrome and Alzheimer's disease brains may contribute to some pathological features, including synaptic dysfunction and cognitive defect through abnormal phosphorylation of Munc18-1.
authors: Graduate Program in Neuroscience, Institute for Brain Science and Technology (IBST), FIRST Research Group, Inje University, Busan, South Korea.
authors: Jung-Hwa
authors: JH
authors: Park
authors: Min-Su
authors: MS
authors: Jung
authors: Yeun-Soo
authors: YS
authors: Kim
authors: Woo-Joo
authors: WJ
authors: Song
authors: Sul-Hee
authors: SH
authors: Chung
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000493:pharmacokinetics; D000818:Animals; D001921:Brain / Q000378:metabolism; D002461:Cell Line, Transformed; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D051938:Munc18 Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010759:Phosphorus Isotopes / Q000493:pharmacokinetics; D010766:Phosphorylation / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D050827:Syntaxin 1 / Q000378:metabolism*; D013912:Threonine / Q000378:metabolism; D014162:Transfection; D000097603:Dyrk Kinases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000255:Adenosine Triphosphate; D051938:Munc18 Proteins; D009419:Nerve Tissue Proteins; D010759:Phosphorus Isotopes; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D050827:Syntaxin 1; D013912:Threonine; D000097603:Dyrk Kinases; C513072:Apba1 protein, mouse