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Src homology 3 binding sites in the P2Y2 nucleotide receptor interact with Src and regulate activities of Src, proline-rich tyrosine kinase 2, and growth factor receptors.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2004 Feb 27; Vol. 279 (9), pp. 8212-8. Date of Electronic Publication: 2003 Dec 11. - Publication Year :
- 2004
-
Abstract
- Many G protein-coupled receptors activate growth factor receptors, although the mechanisms controlling this transactivation are unclear. We have identified two proline-rich, SH3 binding sites (PXXP) in the carboxyl-terminal tail of the human P2Y(2) nucleotide receptor that directly associate with the tyrosine kinase Src in protein binding assays. Furthermore, Src co-precipitated with the P2Y(2) receptor in 1321N1 astrocytoma cells stimulated with the P2Y(2) receptor agonist UTP. A mutant P2Y(2) receptor lacking the PXXP motifs was found to stimulate calcium mobilization and serine/threonine phosphorylation of the Erk1/2 mitogen-activated protein kinases, like the wild-type receptor, but was defective in its ability to stimulate tyrosine phosphorylation of Src and Src-dependent tyrosine phosphorylation of the proline-rich tyrosine kinase 2, epidermal growth factor receptor (EGFR), and platelet-derived growth factor receptor. Dual immunofluorescence labeling of the P2Y(2) receptor and the EGFR indicated that UTP caused an increase in the co-localization of these receptors in the plasma membrane that was prevented by the Src inhibitor PP2. Together, these data suggest that agonist-induced binding of Src to the SH3 binding sites in the P2Y(2) receptor facilitates Src activation, which recruits the EGFR into a protein complex with the P2Y(2) receptor and allows Src to efficiently phosphorylate the EGFR.
- Subjects :
- Amino Acid Sequence
Animals
Astrocytoma
Binding Sites
Calcium metabolism
Cell Membrane chemistry
Fluorescent Antibody Technique
Focal Adhesion Kinase 2
Humans
Mitogen-Activated Protein Kinase 1 metabolism
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinases metabolism
Molecular Sequence Data
Mutagenesis
PC12 Cells
Peptide Fragments chemistry
Peptide Fragments metabolism
Phosphorylation
Pyrimidines pharmacology
Rats
Receptors, Platelet-Derived Growth Factor metabolism
Receptors, Purinergic P2 genetics
Receptors, Purinergic P2Y2
Transfection
Tumor Cells, Cultured
Uridine Triphosphate pharmacology
src-Family Kinases antagonists & inhibitors
ErbB Receptors metabolism
Protein-Tyrosine Kinases metabolism
Receptors, Purinergic P2 chemistry
Receptors, Purinergic P2 metabolism
src Homology Domains
src-Family Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 279
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 14670955
- Full Text :
- https://doi.org/10.1074/jbc.M312230200