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Vol. 17, Issue 11, 4846-4855, November 2006

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Loss of T-Cell Protein Tyrosine Phosphatase Induces Recycling of the Platelet-derived Growth Factor (PDGF) -Receptor but Not the PDGF -Receptor

Susann Karlsson^*, Katarzyna Kowanetz^*,, Åsa Sandin, Camilla Persson^*,, Arne Östman, Carl-Henrik Heldin^*, and Carina Hellberg^*

*Ludwig Institute for Cancer Research, Uppsala University Biomedical Center, S-751 24 Uppsala, Sweden; and Department of Pathology-Oncology, Cancer Center Karolinska, Karolinska Institute, S-171 76 Stockholm, Sweden

Submitted April 13, 2006; Revised August 22, 2006; Accepted August 31, 2006
Monitoring Editor: Anne Ridley

We have previously shown that the T-cell protein tyrosine phosphatase (TC-PTP) dephosphorylates the platelet-derived growth factor (PDGF) -receptor. Here, we show that the increased PDGF -receptor phosphorylation in TC-PTP knockout (ko) mouse embryonic fibroblasts (MEFs) occurs primarily on the cell surface. The increased phosphorylation is accompanied by a TC-PTP–dependent, monensin-sensitive delay in clearance of cell surface PDGF -receptors and delayed receptor degradation, suggesting PDGF -receptor recycling. Recycled receptors could also be directly detected on the cell surface of TC-PTP ko MEFs. The effect of TC-PTP depletion was specific for the PDGF -receptor, because PDGF -receptor homodimers were cleared from the cell surface at the same rate in TC-PTP ko MEFs as in wild-type MEFs. Interestingly, PDGF -receptor heterodimers were recycling. Analysis by confocal microscopy revealed that, in TC-PTP ko MEFs, activated PDGF -receptors colocalized with Rab4a, a marker for rapid recycling. In accordance with this, transient expression of a dominant-negative Rab4a construct increased the rate of clearance of cell surface receptors on TC-PTP ko MEFs. Thus, loss of TC-PTP specifically redirects the PDGF -receptor toward rapid recycling, which is the first evidence of differential trafficking of PDGF receptor family members.

This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/) on September 15, 2006.

Present addresses: Genentech, Department of Molecular Oncology, 94080 South San Francisco, CA 94080-4990;

Karolinska Institutet, MBB/SGC, S-171 77 Stockholm, Sweden.

Address correspondence to: Carina Hellberg (carina.hellberg{at}licr.uu.se)

Abbreviations used: MEF, mouse embryonic fibroblast; PDGF, platelet-derived growth factor; TC-PTP, T-cell protein tyrosine phosphatase.

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