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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.

Pubmed ID: 12893833


  • Takahashi T
  • Yamashita H
  • Nagano Y
  • Nakamura T
  • Ohmori H
  • Avraham H
  • Avraham S
  • Yasuda M
  • Matsumoto M


The Journal of biological chemistry

Publication Data

October 24, 2003

Associated Grants


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