Identification and characterization of a novel Pyk2/related adhesion focal tyrosine kinase-associated protein that inhibits alpha-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.
Mesh Terms:
Adaptor Proteins, Vesicular Transport, Amino Acid Sequence, Brain Chemistry, Carrier Proteins, Cloning, Molecular, Focal Adhesion Kinase 2, Humans, Intracellular Signaling Peptides and Proteins, Molecular Sequence Data, Nerve Tissue Proteins, Osmotic Pressure, Phosphorylation, Protein Binding, Protein-Tyrosine Kinases, Synucleins, Tissue Distribution, Two-Hybrid System Techniques, alpha-Synuclein, src-Family Kinases
Adaptor Proteins, Vesicular Transport, Amino Acid Sequence, Brain Chemistry, Carrier Proteins, Cloning, Molecular, Focal Adhesion Kinase 2, Humans, Intracellular Signaling Peptides and Proteins, Molecular Sequence Data, Nerve Tissue Proteins, Osmotic Pressure, Phosphorylation, Protein Binding, Protein-Tyrosine Kinases, Synucleins, Tissue Distribution, Two-Hybrid System Techniques, alpha-Synuclein, src-Family Kinases
J. Biol. Chem.
Date: Oct. 24, 2003
PubMed ID: 12893833
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