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Loss of T-Cell Protein Tyrosine Phosphatase Induces Recycling of the Platelet-derived Growth Factor (PDGF) beta-Receptor but Not the PDGF {alpha}-Receptor
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.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
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2006 (English)In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 17, no 11, 4846-4855 p.Article in journal (Refereed) Published
Abstract [en]

We have previously shown that the T-cell protein tyrosine phosphatase (TC-PTP) dephosphorylates the platelet-derived growth factor (PDGF) beta-receptor. Here, we show that the increased PDGF beta-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 beta-receptors and delayed receptor degradation, suggesting PDGF beta-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 beta-receptor, because PDGF alpha-receptor homodimers were cleared from the cell surface at the same rate in TC-PTP ko MEFs as in wild-type MEFs. Interestingly, PDGF alphabeta-receptor heterodimers were recycling. Analysis by confocal microscopy revealed that, in TC-PTP ko MEFs, activated PDGF beta-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 beta-receptor toward rapid recycling, which is the first evidence of differential trafficking of PDGF receptor family members.

Place, publisher, year, edition, pages
2006. Vol. 17, no 11, 4846-4855 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-83489DOI: 10.1091/mbc.E06-04-0306ISI: 000241993500023PubMedID: 16971512OAI: oai:DiVA.org:uu-83489DiVA: diva2:111397
Available from: 2006-11-03 Created: 2006-11-03 Last updated: 2017-12-14Bibliographically approved
In thesis
1. T-Cell Protein Tyrosine Phosphatase, a Regulator of the PDGF Signaling Pathway
Open this publication in new window or tab >>T-Cell Protein Tyrosine Phosphatase, a Regulator of the PDGF Signaling Pathway
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Platelet-derived growth factor (PDGF) is a potent stimulator of cell growth, survival and motility. PDGF exerts its function by binding to specific tyrosine kinase receptors, initiating receptor auotphosphorylation and initiation of specific signaling pathways that regulates the cellular response. It is critical that these signals can be modulated and terminated, since over-activation of signaling pathways are often found in diseases, such as cancer. Protein tyrosine phosphatases (PTPs) counteract the tyrosine kinases by dephosphorylating proteins, thereby playing a crucial role in the control of signaling events. The aim of this thesis has been to study the regulation of PDGF receptor signaling by the T-cell protein tyrosine phosphatase (TC-PTP).

In the first two studies, we demonstrated that loss of TC-PTP specifically redirected the PDGF β-receptor towards a rapid Rab4a-dependent recycling after ligand-induced internalization. Furthermore, we found that the sorting of activated PDGF β-receptor into the recycling pathway was dependent on sequential PKCα and Rab4a activation. Since the PDGF α-receptor did not recycle in the absence of TC-PTP, this study displays the first evidence of differences in trafficking of the PDGF receptor family members. PDGF β-receptor recycling was also induced by activating PKCα through the LPA receptor. The LPA-induced PDGF β-receptor recycling correlated with increased receptor phosphorylation and cell migration at low concentrations of PDGF-BB. The data suggests that PKCα activation could serve as a point of cross-talk between receptor families, regulating the duration and magnitude of PDGF β-receptor signaling.

In the last study, we searched for novel substrates for TC-PTP downstream of the PDGF β-receptor, and identified the pyruvate kinase M2, PK-M2, as a possible substrate. PK-M2 is expressed in cells that proliferate rapidly, including tumor cells. Our data suggests that TC-PTP can interact with the glycolytic complex, affecting the activity of PK-M2 and hence, altering the glucose metabolism for proliferating tumor cells.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 46 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 477
Keyword
PDGF, TC-PTP, receptor trafficking, PK-M2
National Category
Cell and Molecular Biology
Research subject
Molecular Cellbiology
Identifiers
urn:nbn:se:uu:diva-107674 (URN)978-91-554-7595-6 (ISBN)
Public defence
2009-10-02, B42, BMC, Husargatan 3, Uppsala, 09:15 (English)
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Available from: 2009-09-23 Created: 2009-08-23 Last updated: 2009-09-23Bibliographically approved

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Karlsson, SusannHeldin, Carl-HenrikHellberg, Carina

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