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

Autor: Lars Rönnstrand, Charlotte Rorsman, Ulla Engström, Ulf Hellman, Anders Kallin, Ann-Kristin Arvidsson, Christer Wernstedt, Carl-Henrik Heldin
Předmět:
Cancer Research
animal structures
Swine
Molecular Sequence Data
Becaplermin
Protein Tyrosine Phosphatase
Non-Receptor Type 11
Protein tyrosine phosphatase
Transfection
Receptor
Platelet-Derived Growth Factor beta
Mice
Genetics
Animals
Receptors
Platelet-Derived Growth Factor
Amino Acid Sequence
Phosphorylation
Tyrosine
Phosphotyrosine
Protein kinase A
Molecular Biology
Cells
Cultured
Mitogen-Activated Protein Kinase 1
Platelet-Derived Growth Factor
Binding Sites
biology
Chemotaxis
Protein Tyrosine Phosphatase
Non-Receptor Type 6
Autophosphorylation
Intracellular Signaling Peptides and Proteins
Proto-Oncogene Proteins c-sis
Molecular biology
Enzyme Activation
Mitogen-activated protein kinase
Calcium-Calmodulin-Dependent Protein Kinases
Mutagenesis
Site-Directed
ras Proteins
biology.protein
Endothelium
Vascular
Guanosine Triphosphate
Protein Tyrosine Phosphatases
Protein Processing
Post-Translational
Platelet-derived growth factor receptor
Signal Transduction
Zdroj: Lund University
Popis: 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.
Databáze: OpenAIRE
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