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Molecular and Cellular Biology, March 2004, p. 2190-2201, Vol. 24, No. 5
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.5.2190-2201.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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,{dagger} Arne Östman,1 and Carina Hellberg1*

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 C{gamma}1 binding site Y1021, previously implicated in chemotaxis, displayed the largest increase in phosphorylation. The increase in Y1021 phosphorylation was accompanied by increased phospholipase C{gamma}1 activity and migratory hyperresponsiveness to PDGF. PDGF ß receptor tyrosine phosphorylation in PTP-1B ko MEFs but not in PTP{varepsilon} 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.

* Corresponding author. Mailing address: Ludwig Institute for Cancer Research, Uppsala Branch, Biomedical Center, Husargatan 3, Box 595, S-751 24 Uppsala, Sweden. Phone: 46-18-160415. Fax: 46-18-160420. E-mail: Carina.Hellberg{at}LICR.uu.se.

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

Molecular and Cellular Biology, March 2004, p. 2190-2201, Vol. 24, No. 5
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.5.2190-2201.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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