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Site-selective regulation of platelet-derived growth factor beta receptor tyrosine phosphorylation by T-cell protein tyrosine phosphatase.

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Author

  • Camilla Persson
  • Catrine Sävenhed
  • Annie Bourdeau
  • Michel L Tremblay
  • Boyka Markova
  • Frank D Böhmer
  • Fawaz G Haj
  • Benjamin G Neel
  • Ari Elson
  • Carl-Henrik Heldin
  • Lars Rönnstrand
  • Arne Ostman
  • Carina Hellberg
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Summary, in English

The platelet-derived growth factor (PDGF) ß receptor mediates mitogenic and chemotactic signals. Like other tyrosine kinase receptors, the PDGF ß receptor is negatively regulated by protein tyrosine phosphatases (PTPs). To explore whether T-cell PTP (TC-PTP) negatively regulates the PDGF ß receptor, we compared PDGF ß receptor tyrosine phosphorylation in wild-type and TC-PTP knockout (ko) mouse embryos. PDGF ß receptors were hyperphosphorylated in TC-PTP ko embryos. Fivefold-higher ligand-induced receptor phosphorylation was observed in TC-PTP ko mouse embryo fibroblasts (MEFs) as well. Reexpression of TC-PTP partly abolished this difference. As determined with site-specific phosphotyrosine antibodies, the extent of hyperphosphorylation varied among different autophosphorylation sites. The phospholipase C1 binding site Y1021, previously implicated in chemotaxis, displayed the largest increase in phosphorylation. The increase in Y1021 phosphorylation was accompanied by increased phospholipase C1 activity and migratory hyperresponsiveness to PDGF. PDGF ß receptor tyrosine phosphorylation in PTP-1B ko MEFs but not in PTP ko MEFs was also higher than that in control cells. This increase occurred with a site distribution different from that seen after TC-PTP depletion. PDGF-induced migration was not increased in PTP-1B ko cells. In summary, our findings identify TC-PTP as a previously unrecognized negative regulator of PDGF ß receptor signaling and support the general notion that PTPs display site selectivity in their action on tyrosine kinase receptors.

Copyright © 2004, American Society for Microbiology. All Rights Reserved

Publishing year

2004

Language

English

Pages

201-2190

Publication/Series

Molecular and Cellular Biology

Volume

24

Issue

5

Document type

Journal article

Publisher

American Society for Microbiology

Topic

  • Medicinal Chemistry

Status

Published

ISBN/ISSN/Other

  • ISSN: 0270-7306