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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

Rönnstrand, Lars LU ; Arvidsson, Ann-Kristin; Kallin, Anders; Rorsman, Charlotte; Hellman, Ulf; Engström, Ulla; Wernstedt, Christer and Heldin, Carl-Henrik (1999) In Oncogene 18(25). p.3696-3702
Abstract
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... (More)
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. (Less)
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@article{fa3b48cc-750e-45cf-ad1b-45a656793a0b,
  abstract     = {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.},
  author       = {Rönnstrand, Lars and Arvidsson, Ann-Kristin and Kallin, Anders and Rorsman, Charlotte and Hellman, Ulf and Engström, Ulla and Wernstedt, Christer and Heldin, Carl-Henrik},
  issn         = {1476-5594},
  keyword      = {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},
  language     = {eng},
  number       = {25},
  pages        = {3696--3702},
  publisher    = {Nature Publishing Group},
  series       = {Oncogene},
  title        = {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},
  volume       = {18},
  year         = {1999},
}