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Inhibition of Platelet-derived Growth Factor-BB-induced Receptor Activation and Fibroblast Migration by Hyaluronan Activation of CD44
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.
2006 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 281, no 36, 26512-26519 p.Article in journal (Refereed) Published
Abstract [en]

The extracellular matrix molecule hyaluronan was found to suppress platelet-derived growth factor (PDGF) beta-receptor activation and PDGF-BB-induced migration of primary human dermal fibroblasts. The suppressive effect of hyaluronan was neutralized by a monoclonal antibody that specifically inhibits hyaluronan binding to its receptor CD44. Moreover, co-immunoprecipitation experiments showed that the PDGF beta-receptor and CD44 can form a complex. Interestingly, the inhibitory effect of hyaluronan on PDGF beta-receptor activation was not seen in the presence of the tyrosine phosphatase inhibitor pervanadate. Our observations suggest that hyaluronan suppresses PDGF beta-receptor activation by recruiting a CD44-associated tyrosine phosphatase to the receptor.

Place, publisher, year, edition, pages
2006. Vol. 281, no 36, 26512-26519 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-94340DOI: 10.1074/jbc.M605607200ISI: 000240249500069PubMedID: 16809345OAI: oai:DiVA.org:uu-94340DiVA: diva2:168159
Available from: 2006-04-27 Created: 2006-04-27 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Effect of Hyaluronan-activation of CD44 on Cell Signaling and Tumorigenesis
Open this publication in new window or tab >>Effect of Hyaluronan-activation of CD44 on Cell Signaling and Tumorigenesis
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Hyaluronan (HA), a structural component in the extracellular matrix (ECM), has been recognized as a signaling molecule. It is important during various biological activities such as embryogenesis, angiogenesis, wound healing and tumor progression. Increased amount of hyaluronan during embryonic development is necessary for cell migration and differentiation, but the increased production of hyaluronan by tumor cells or tissue fibroblasts is correlated to poor prognosis for tumor progression and chronic inflammation, respectively. Therefore, understanding the mechanisms regulating HA-enriched matrices and the roles of HA in the biological functions is of fundamental biological importance.

Four novel findings are described in this thesis: (1) HA fragments (HA12) and the known angiogenic factor FGF-2 promote endothelial cell differentiation by induction of common but also distinct sets of genes, particularly, upregulation of the chemokine CXCL1/GRO1 gene is necessary for HA12-induced angiogenesis and this effect is dependent on CD44 activation. (2) High concentrations of hyaluronan suppress PDGF-BB-induced fibroblasts migration and PDGFRβ tyrosine phosphorylation upon activation of hyaluronan receptor CD44, probably by recruiting a CD44-associated phosphatase to the PDGFRβ. (3) PDGF-BB stimulates HAS2 transcriptional activity and HA synthesis through upregulation of MAP kinase and PI3 kinase signaling pathways in human dermal fibroblasts. (4) Specific suppression of HAS2 gene in the invasive breast cancer cell line Hs578T by RNA interference (RNAi) leads to a less aggressive phenotype of breast tumor cells. This suppressive effect can be reversed by exogenously added hyaluronan.

In conclusion, binding of hyaluronan to CD44 plays an important role in cell signaling, inflammation and tumor progression. Further studies are required to elucidate the molecular mechanisms through which hyaluronan levels are regulated under physiological or pathological conditions, and to explore compounds involved in hyaluronan accumulation and activity as targets for therapies of chronic inflammation and tumors.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 38 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 142
Keyword
Biomedicine, Hyaluronan, CD44, growth factors, chemokines, tumorigenesis, wound healing, cell signaling, Biomedicin
Identifiers
urn:nbn:se:uu:diva-6802 (URN)91-554-6537-4 (ISBN)
Public defence
2006-05-22, Room B21, BMC, Uppsala, 13:15
Opponent
Supervisors
Available from: 2006-04-27 Created: 2006-04-27Bibliographically approved

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Heldin, Carl-HenrikHeldin, Paraskevi

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