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

http://www.ncbi.nlm.nih.gov/pubmed/11943772

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 RIS Download

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

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