SHP-2 binds to Tyr763 and Tyr1009 in the PDGF beta-receptor and mediates PDGF-induced activation of the Ras/MAP kinase pathway and chemotaxis
Författare
Summary, in English
Activation of the beta-receptor for platelet-derived growth factor (PDGF) by its ligand leads to autophosphorylation on a number of tyrosine residues. Here we show that Tyr763 in the kinase insert region is a novel autophosphorylation site, which after phosphorylation binds the protein tyrosine phosphatase SHP-2. SHP-2 has also previously been shown to bind to phosphorylated Tyr1009 in the PDGF beta-receptor. Porcine aortic endothelial (PAE) cells transfected with a PDGF beta-receptor in which Tyr763 and Tyr1009 were mutated to phenylalanine residues failed to associate with SHP-2 after ligand stimulation. Moreover, PDGF-BB-induced Ras GTP-loading and Erk2 activation were severely compromised in the receptor mutant. Whereas the mitogenic response to PDGF-BB remained at the same level as in cells expressing wild-type PDGF beta-receptor, chemotaxis induced by PDGF-BB was significantly decreased in the case of the Y763F/Y1009F mutant cells, suggesting an important role for SHP-2 in chemotactic signaling.
Publiceringsår
1999
Språk
Engelska
Sidor
3696-3702
Publikation/Tidskrift/Serie
Oncogene
Volym
18
Issue
25
Dokumenttyp
Artikel i tidskrift
Förlag
Nature Publishing Group
Ämne
- Medicinal Chemistry
Nyckelord
- Non-Receptor Type 6 Protein Tyrosine Phosphatases/*metabolism Receptor
- Platelet-Derived Growth Factor beta Receptors
- Post-Translational Protein Tyrosine Phosphatase
- Non-Receptor Type 11 Protein Tyrosine Phosphatase
- Site-Directed Phosphorylation Phosphotyrosine/metabolism Platelet-Derived Growth Factor/pharmacology *Protein Processing
- Vascular/metabolism Enzyme Activation Guanosine Triphosphate/metabolism Intracellular Signaling Peptides and Proteins Mice Mitogen-Activated Protein Kinase 1 Molecular Sequence Data Mutagenesis
- Cultured *Chemotaxis Endothelium
- Amino Acid Sequence Animals Binding Sites Calcium-Calmodulin-Dependent Protein Kinases/metabolism/*physiology Cells
- Platelet-Derived Growth Factor/chemistry/*metabolism *Signal Transduction Swine Transfection Tyrosine/*metabolism ras Proteins/*physiology
Status
Published
ISBN/ISSN/Övrigt
- ISSN: 1476-5594