Activated Fyn phosphorylates alpha-synuclein at tyrosine residue 125.
alpha-Synuclein is a presynaptic protein of unknown function that has been implicated in the pathogenesis of several neurodegenerative diseases, including Parkinson's and Alzheimer's diseases. To gain insight into the functions of alpha-synuclein, we sought protein kinases that phosphorylate alpha-synuclein in the central nervous system. In contrast to Lyn, PYK2, FAK, MAPK/ERK1, SAPK/JNK, and Cdk5, only Fyn could phosphorylate alpha-synuclein. In addition, A30P and A53T mutations did not affect the phosphorylation of alpha-synuclein by Fyn. Mutation analysis revealed that activated Fyn phosphorylates specifically tyrosine residue 125 of alpha-synuclein. The distribution of alpha-synuclein and Fyn expression was similar in various parts of the brain and was colocalized in subcellular structures. Since Fyn regulates various signal transduction pathways in the central nervous system and plays an essential role in the neuronal cell differentiation, survival, and plasticity, results of this paper indicate that phosphorylation of alpha-synuclein might be involved in one of the Fyn-mediated signaling pathways in neuronal cells.
Nakamura
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T
Third Department of Internal Medicine, Hiroshima University School of Medicine, 1-2-3 Kasumi, Minamiku, Hiroshima, 734-8551, Japan.
Yamashita
H
H
Takahashi
T
T
Nakamura
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S
D000818:Animals; D015152:Blotting, Northern; D001921:Brain / Q000378:metabolism; D019556:COS Cells; D002490:Central Nervous System / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000378:metabolism; D004789:Enzyme Activation; D051417:Focal Adhesion Kinase 1; D051418:Focal Adhesion Kinase 2; D051416:Focal Adhesion Protein-Tyrosine Kinases; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D048052:Mitogen-Activated Protein Kinase 3; D048056:Mitogen-Activated Protein Kinase 9; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation; D011233:Precipitin Tests; D011493:Protein Kinase C / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D051076:Proto-Oncogene Proteins c-fyn; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D051843:Synucleins; D013997:Time Factors; D014018:Tissue Distribution; D014443:Tyrosine / Q000378:metabolism*; D051844:alpha-Synuclein; D019061:src-Family Kinases / Q000378:metabolism
D018076:DNA, Complementary; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; D014443:Tyrosine; D005982:Glutathione Transferase; D048056:Mitogen-Activated Protein Kinase 9; D011505:Protein-Tyrosine Kinases; C494957:FYN protein, human; D051417:Focal Adhesion Kinase 1; D051418:Focal Adhesion Kinase 2; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D051076:Proto-Oncogene Proteins c-fyn; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D051360:Cyclin-Dependent Kinase 5; D011493:Protein Kinase C; C495905:CDK5 protein, human; D018844:Cyclin-Dependent Kinases; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases