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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

Författare

  • Lars Rönnstrand
  • Ann-Kristin Arvidsson
  • Anders Kallin
  • Charlotte Rorsman
  • Ulf Hellman
  • Ulla Engström
  • Christer Wernstedt
  • Carl-Henrik Heldin

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