Identification and Characterization of a Novel Pyk2/Related Adhesion Focal Tyrosine Kinase-associated Protein That Inhibits α-Synuclein Phosphorylation
Copyright policy )Identification and Characterization of a Novel Pyk2/Related Adhesion Focal Tyrosine Kinase-associated Protein That Inhibits α-Synuclein Phosphorylation
alpha-Synuclein is a presynaptic protein involved in the pathogenesis of several neurodegenerative diseases, such as Parkinson's disease. Pyk2/related adhesion focal tyrosine kinase (RAFTK) tyrosine kinase is an upstream regulator of Src family kinases in the central nervous system that is involved in alpha-synuclein phosphorylation. The present study reports the cloning and characterization of a novel adaptor protein, Pyk2/RAFTK-associated protein (PRAP), that specifically binds to Pyk2/RAFTK and inhibits alpha-synuclein tyrosine phosphorylation. PRAP contains a coiled-coil domain, a pleckstrin homology domain, and a SH3 domain; the SH3 domain binds to the proline-rich domain of Pyk2/RAFTK. PRAP was observed to be present throughout the brain, including substantia nigra dopaminergic neurons, in which it localized to the cytoplasm. PRAP was found to function as a substrate for Src family kinases, such as c-Src or Fyn, but not for Pyk2/RAFTK. Hyperosmotic stress induced phosphorylation of tyrosine 125 of alpha-synuclein via Pyk2/RAFTK, which acted through Src family kinases. Such phosphorylation was inhibited by PRAP expression, suggesting that PRAP negatively regulates alpha-synuclein phosphorylation following cell stress. In conclusion, PRAP functions as a downstream target for Pyk2/RAFTK and plays a role in alpha-synuclein phosphorylation.
- Beth Israel Deaconess Medical Center United States
- Hiroshima University Japan
- Hiroshima International University Japan
- International University Cambodia
Brain Chemistry, Molecular Sequence Data, Intracellular Signaling Peptides and Proteins, Synucleins, Nerve Tissue Proteins, Protein-Tyrosine Kinases, Adaptor Proteins, Vesicular Transport, Focal Adhesion Kinase 2, src-Family Kinases, Osmotic Pressure, Two-Hybrid System Techniques, alpha-Synuclein, Humans, Tissue Distribution, Amino Acid Sequence, Cloning, Molecular, Phosphorylation, Carrier Proteins, Protein Binding
Brain Chemistry, Molecular Sequence Data, Intracellular Signaling Peptides and Proteins, Synucleins, Nerve Tissue Proteins, Protein-Tyrosine Kinases, Adaptor Proteins, Vesicular Transport, Focal Adhesion Kinase 2, src-Family Kinases, Osmotic Pressure, Two-Hybrid System Techniques, alpha-Synuclein, Humans, Tissue Distribution, Amino Acid Sequence, Cloning, Molecular, Phosphorylation, Carrier Proteins, Protein Binding
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