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Site-selective regulation of platelet-derived growth factor beta receptor tyrosine phosphorylation by T-cell protein tyrosine phosphatase
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
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2004 (English)In: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 24, no 5, 2190-2201 p.Article in journal (Refereed) Published
Abstract [en]

The platelet-derived growth factor (PDGF) beta receptor mediates mitogenic and chemotactic signals. Like other tyrosine kinase receptors, the PDGF beta receptor is negatively regulated by protein tyrosine phosphatases (PTPs). To explore whether T-cell PTP (TC-PTP) negatively regulates the PDGF beta receptor, we compared PDGF beta receptor tyrosine phosphorylation in wild-type and TC-PTP knockout (ko) mouse embryos. PDGF beta 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 Cgamma1 binding site Y1021, previously implicated in chemotaxis, displayed the largest increase in phosphorylation. The increase in Y1021 phosphorylation was accompanied by increased phospholipase Cgamma1 activity and migratory hyperresponsiveness to PDGF. PDGF beta receptor tyrosine phosphorylation in PTP-1B ko MEFs but not in PTPepsilon 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 beta receptor signaling and support the general notion that PTPs display site selectivity in their action on tyrosine kinase receptors.

Place, publisher, year, edition, pages
2004. Vol. 24, no 5, 2190-2201 p.
Keyword [en]
Animals, Antibodies; Phospho-Specific/metabolism, Cell Movement/physiology, Fibroblasts/cytology/metabolism, Isoenzymes/genetics/metabolism, Mice, Mice; Knockout, Phosphorylation, Protein-Tyrosine-Phosphatase/genetics/*metabolism, Receptor; Platelet-Derived Growth Factor beta/genetics/*metabolism, Research Support; Non-U.S. Gov't, Signal Transduction/physiology, Tyrosine/*metabolism
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Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-72912DOI: 10.1128/MCB.24.5.2190-2201.2004PubMedID: 14966296OAI: oai:DiVA.org:uu-72912DiVA: diva2:100823
Available from: 2005-05-30 Created: 2005-05-30 Last updated: 2013-11-05Bibliographically approved

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Heldin, Carl-HenrikHellberg, Carina

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