Phosphorylation of Munc18-1 by Dyrk1A regulates its interaction with Syntaxin 1 and X11α

• Published in: Journal of neurochemistry 2012-09, Vol.122 (5), p.1081-1091
• Main Authors: Park, Jung-Hwa, Jung, Min-Su, Kim, Yeun-Soo, Song, Woo-Joo, Chung, Sul-Hee
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Adenosine Triphosphate - pharmacokinetics; Adult and adolescent clinical studies; Alzheimer's disease; Amyloid precursor protein; Animals; beta -Amyloid; Biological and medical sciences; Brain; Brain - metabolism; Cell Line, Transformed; Cognitive ability; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Down's syndrome; Dyrk Kinases; Dyrk1A; Exocytosis; Humans; Immunoprecipitation; Intellectual deficiency; Medical sciences; Mental retardation; Mice; Mice, Knockout; Munc18 Proteins - deficiency; Munc18 Proteins - genetics; Munc18 Proteins - metabolism; Munc18-1; Mutation - physiology; N-Ethylmaleimide-sensitive protein; Nerve Tissue Proteins - metabolism; Neurodegenerative diseases; Neurology; Neurotransmitter release; Phosphorus Isotopes - pharmacokinetics; Phosphorylation; Phosphorylation - genetics; Protein Binding - drug effects; Protein Binding - genetics; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Protein Serine-Threonine Kinases - pharmacology; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Protein-Tyrosine Kinases - pharmacology; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Synaptic vesicles; Syntaxin; syntaxin 1; Syntaxin 1 - metabolism; Threonine - metabolism; Transfection; Transgenic mice; X11α
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2012.07861.x

J. Neurochem. (2012) 122, 1081–1091. 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 Thr479 residue. The phosphorylation of Munc18‐1 at Thr479 by Dyrk1A stimulated binding of Munc18‐1 to Syntaxin 1 and X11α. Furthermore, the levels of phospho‐Thr479‐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. Phosphorylation of Munc18‐1 by Dyrk1AMunc18‐1, a central regulator of neurotransmitter release, interacts with Syntaxin and X11α. In this study, we showed that Dyrk1A phosphorylates Munc18‐1 at the Thr479 residue in vitro and in vivo. This phosphorylation stimulates the binding of Munc18‐1 to Syntaxin 1 and X11α, supporting the potential role of Dyrk1A‐mediated phosphorylation in vesicle trafficking.