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Association of Fyn and Lyn with the proline-rich domain of glycoprotein VI regulates intracellular signaling.

The glycoprotein VI (GPVI)-Fc receptor (FcR) gamma-chain complex, a key activatory receptor for collagen on platelet surface membranes, is constitutively associated with the Src family kinases Fyn and Lyn. Molecular cloning of GPVI has revealed the presence of a proline-rich domain in the sequence of GPVI cytoplasmic tail which has the consensus for interaction with the Src homology 3 (SH3) domains of Fyn and Lyn. A series of in vitro experiments demonstrated the ability of the SH3 domains of both Src kinases to bind the proline-rich domain of GPVI. Furthermore, depletion of the proline-rich domain in GPVI (Pro(-)-GPVI) prevented binding of Fyn and Lyn and markedly reduced phosphorylation of FcR gamma-chain in transiently transfected COS-7 cells, but did not affect the association of the gamma-chain with GPVI. Jurkat cells stably transfected with wild type GPVI show robust increases in tyrosine phosphorylation and intracellular Ca2+ in response to the snake venom convulxin that targets GPVI. Importantly, convulxin is not able to activate cells transfected with Pro(-)-GPVI, even though the association with the immunoreceptor tyrosine-based activation motif-containing chains is maintained. These findings demonstrate that the proline-rich domain of GPVI mediates the association with Fyn/Lyn via their SH3 domain and that this interaction initiates activation signals through GPVI.

Pubmed ID: 11943772

Authors

  • Suzuki-Inoue K
  • Tulasne D
  • Shen Y
  • Bori-Sanz T
  • Inoue O
  • Jung SM
  • Moroi M
  • Andrews RK
  • Berndt MC
  • Watson SP

Journal

The Journal of biological chemistry

Publication Data

June 14, 2002

Associated Grants

None

Mesh Terms

  • Animals
  • Blood Platelets
  • COS Cells
  • Calcium
  • Cell Line
  • DNA, Complementary
  • Escherichia coli
  • Flow Cytometry
  • Glutathione Transferase
  • Humans
  • Immunoblotting
  • Ligands
  • Mutagenesis, Site-Directed
  • Phosphorylation
  • Platelet Membrane Glycoproteins
  • Precipitin Tests
  • Proline
  • Protein Binding
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-fyn
  • Recombinant Fusion Proteins
  • Signal Transduction
  • Time Factors
  • Transfection
  • src Homology Domains
  • src-Family Kinases