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Site-Selective Regulation of Platelet-Derived Growth Factor ß Receptor Tyrosine Phosphorylation by T-Cell Protein Tyrosine Phosphatase

Camilla Persson,¹ Catrine Sävenhed,¹ Annie Bourdeau,² Michel L. Tremblay,² Boyka Markova,³ Frank D. Böhmer,³ Fawaz G. Haj,⁴ Benjamin G. Neel,⁴ Ari Elson,⁵ Carl-Henrik Heldin,¹ Lars Rönnstrand,^1, Arne Östman,¹ and Carina Hellberg^1*

Ludwig Institute for Cancer Research, Uppsala Branch, Biomedical Center, S-751 24 Uppsala, Sweden,¹ McGill Cancer Center, Montreal, Quebec H3G 1Y6, Canada,² Institute of Molecular Cell Biology, Medical Faculty, Friedrich Schiller University, D-07747 Jena, Germany,³ Cancer Biology Program, Division of Hematology-Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215,⁴ Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel⁵

Received 25 August 2003/ Returned for modification 8 October 2003/ Accepted 8 December 2003

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.

Present address: Division of Experimental Clinical Chemistry, Lund University, Malmö University Hospital, SE-205 02 Malmö, Sweden.

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