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Signaling via PI3K is required for PDGF BB-induced cofilin dephosphorylation and collagen gel contraction.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. (Rubin)
(English)Manuscript (Other academic)
URN: urn:nbn:se:uu:diva-102347OAI: oai:DiVA.org:uu-102347DiVA: diva2:214739
Available from: 2009-05-06 Created: 2009-05-06 Last updated: 2010-01-14
In thesis
1. Intra- and Extracellular Modulation of Integrin-directed Connective Tissue Cell Contraction
Open this publication in new window or tab >>Intra- and Extracellular Modulation of Integrin-directed Connective Tissue Cell Contraction
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

All blood vessels in the microvasculature are embedded in loose connective tissue, which regulates the transport of fluid to and from tissues. The intersti-tial fluid pressure (IFP) is one of the forces that control this transport. A lowering of IFP in vivo results in an increased transport of fluid from the circulation into the underhydrated connective tissues, resulting in edema formation. During homeostasis, contractile connective tissue cells exert a tension on the connective tissue fibrous network by binding with β1 in-tegrins, thereby actively controlling IFP. During inflammation, the IFP is lowered but platelet-derived growth factor (PDGF)-BB induces an IFP nor-malization dependent on integrin αVβ3. We demonstrate that extracellular proteins from Streptococcus equi subspecies equi modulated cell-mediated and integrin αVβ3-directed collagen gel contraction in vitro. One of these proteins, the collagen- and fibronectin binding FNE, stimulated contraction by a process dependent on fibronectin synthesis. This study identified a pos-sible novel virulence mechanism for bacteria based on the ability of bacteria to modulate the edema response. Another protein, the collagen-binding pro-tein CNE, inhibited contraction and this led to the identification of sites in collagen monomers that potentially are involved in connecting αVβ3 to the collagen network. PDGF-BB and prostaglandin E1 (PGE1) stimulate and inhibit collagen gel contraction in vitro and normalize and lower IFP, respec-tively. We showed that these agents affected both similar and different sets of actin-binding proteins. PDGF-BB stimulated actin cytoskeleton dynamics whereas PGE1 inhibited processes dependent on cytoskeletal motor and adhesive functions, suggesting that these different activities may partly ex-plain the contrasting effects of PGE1 and PDGF-BB on contraction and IFP. Mutation of the phosphatidylinositol 3’-kinase (PI3K), but not phospholipase C (PLC)γ activation site, rendered cells unable to respond to PDGF-BB in contraction and in activation of the actin binding and severing protein cofilin. Ability to activate cofilin after PDGF-BB stimulation correlated with ability to respond to PDGF-BB in contraction, suggesting a role for cofilin in this process downstream of PDGF receptor-activated PI3K. Many proteins can modulate contraction either by affecting the extracellular matrix and cell adhesions or by altering cytoskeletal dynamics. Knowledge on how these proteins might influence IFP is likely to be of clinical importance for treat-ment of inflammatory conditions including anaphylaxis, septic shock and also carcinoma growth.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 64 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 651
Interstitial fluid pressure, PDGF-BB, bacterial proteins, αVβ3 integrin, cytoskeleton
National Category
Biochemistry and Molecular Biology
Research subject
urn:nbn:se:uu:diva-102349 (URN)978-91-554-7546-8 (ISBN)
Public defence
2009-06-12, B22, Uppsala Biomedical Center (BMC), Husargatan 3, Uppsala, 13:15 (English)
Available from: 2009-05-19 Created: 2009-05-06 Last updated: 2009-05-19Bibliographically approved

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van Wieringen, Tijs
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