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Platelet-derived Growth Factor beta-Receptor, Transforming Growth Factor beta Type I Receptor, and CD44 Protein Modulate Each Other's Signaling and Stability
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.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
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2014 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 289, no 28, 19747-19757 p.Article in journal (Refereed) Published
Abstract [en]

Growth factors, such as platelet-derived growth factor BB (PDGF-BB) and transforming growth factor beta(TGF beta), are key regulators of cellular functions, including proliferation, migration, and differentiation. Growth factor signaling is modulated by context-dependent cross-talk between different signaling pathways. We demonstrate in this study that PDGF-BB induces phosphorylation of Smad2, a downstream mediator of the canonical TGF beta pathway, in primary dermal fibroblasts. The PDGF-BB-mediated Smad2 phosphorylation was dependent on the kinase activities of both TGF beta type I receptor (T beta RI) and PDGF beta-receptor (PDGFR beta), and it was prevented by inhibitory antibodies against TGF beta. Inhibition of the activity of the T beta RI kinase greatly reduced the PDGF-BB-dependent migration in dermal fibroblasts. Moreover, we demonstrate that the receptors for PDGF-BB and TGF beta interact physically in primary dermal fibroblasts and that stimulation with PDGF-BB induces internalization not only of PDGFR beta but also of T beta RI. In addition, silencing of PDGFR beta by siRNA decreased the stability of T beta RI and delayed TGF beta-induced signaling. We further show that the hyaluronan receptor CD44 interacts with both PDGFR beta and T beta RI. Depletion of CD44 by siRNA increased signaling via PDGFR beta and T beta RI by stabilizing the receptor proteins. Our data suggest that cross-talk between PDGFR beta and T beta RI occurs in dermal fibroblasts and that CD44 negatively modulates signaling via these receptors.

Place, publisher, year, edition, pages
2014. Vol. 289, no 28, 19747-19757 p.
National Category
Basic Medicine
Identifiers
URN: urn:nbn:se:uu:diva-230095DOI: 10.1074/jbc.M114.547273ISI: 000339326800046OAI: oai:DiVA.org:uu-230095DiVA: diva2:742846
Available from: 2014-09-02 Created: 2014-08-19 Last updated: 2017-12-05Bibliographically approved
In thesis
1. Regulation of Hyaluronan Synthesis and Signaling via CD44 in Cancer
Open this publication in new window or tab >>Regulation of Hyaluronan Synthesis and Signaling via CD44 in Cancer
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Hyaluronan is a ubiquitous glycosaminoglycan which is an important constituent of the extracellular matrix (ECM). In addition to organizing the extracellular matrix and regulating tissue homeostasis, hyaluronan, by binding to its main cell surface receptor CD44, is involved in intracellular signaling pathways regulating major cellular processes during development, wound healing, inflammation and cancer. Accumulation of hyaluronan in cancer promotes progression of the disease and correlates with poor prognosis. This thesis focuses on the regulation of hyaluronan synthesis and its signaling in normal and cancer cells.

Cancer cells in solid tumors are surrounded by stroma, which has an essential role in the growth and metastasis of tumors. Prominent members of the tumor stroma are fibroblasts, which synthesize ECM components, such as hyaluronan, and secrete growth factors, and activate intracellular signaling pathways. We demonstrate a cross-talk between the receptors for platelet-derived growth factor BB (PDGF-BB), transforming growth factor β (TGFβ) and CD44 in dermal fibroblasts. We found that PDGF-BB can activate the Smad signaling pathway downstream of the TGFβ receptor I (TβRI), and that PDGF-BB-induced migration depends on TβRI. CD44 forms a ternary complex with the receptors for PDGF-BB and TGFβ, and negatively regulates their signaling. Furthermore, we demonstrate that TGFβ stimulation of mammary epithelial cells transcriptionally upregulates hyaluronan synthase 2 (HAS2), which is essential for TGFβ-induced epithelial-mesenchymal transition (EMT); in this process, polarized epithelial cells adapt a mesenchymal phenotype which facilitates migration and invasion.

HAS2 protein activity and stability is regulated by posttranslational modifications, including ubiquitination. We investigated the ubiquitination of HAS2 in aggressive breast cancer cells, whose metastasizing capability depends on HAS2-synthesized hyaluronan. We identified two deubiquitinating enzymes, USP4 and USP17, which target HAS2 and affect its activity and stability.

In summary, these studies increase the knowledge about the regulation of hyaluronan production and its role in cancer progression.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. 54 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1291
Keyword
Hyaluronan, CD44, TGFβ, PDGF-BB, cancer, signaling, hyaluronan synthase, epithelial-mesenchymal transition
National Category
Cell and Molecular Biology
Research subject
Biology with specialization in Molecular Biology; Medical Science
Identifiers
urn:nbn:se:uu:diva-312485 (URN)978-91-554-9797-2 (ISBN)
Public defence
2017-03-03, B/B42, Biomedical Centre (BMC), Husargatan 3, Uppsala, 13:15 (English)
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Available from: 2017-02-10 Created: 2017-01-10 Last updated: 2017-02-15

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Mehic, MerimaHeldin, ParaskeviHeldin, Carl-Henrik

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