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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 orcid ; 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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publishing date
type
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subject
keywords
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
in
Oncogene
volume
18
issue
25
pages
3696 - 3702
publisher
Nature Publishing Group
ISSN
1476-5594
language
English
LU publication?
no
additional info
The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Experimental Clinical Chemistry (013016010)
id
fa3b48cc-750e-45cf-ad1b-45a656793a0b (old id 1782672)
date added to LUP
2016-04-04 08:53:49
date last changed
2019-05-22 02:18:28
@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}},
  keywords     = {{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}},
}