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Clustering of β1-integrins induces ERK1/2-dependent αvβ3-mediated collagen gel contraction
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Manuscript (Other academic)
URN: urn:nbn:se:uu:diva-90963OAI: oai:DiVA.org:uu-90963DiVA: diva2:163506
Available from: 2003-10-30 Created: 2003-10-30 Last updated: 2010-01-13Bibliographically approved
In thesis
1. Functional Studies of Collagen-Binding Integrins α2β1 and α11β1: Interplay between Integrins and Platelet-Derived Growth Factor Receptors
Open this publication in new window or tab >>Functional Studies of Collagen-Binding Integrins α2β1 and α11β1: Interplay between Integrins and Platelet-Derived Growth Factor Receptors
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Integrins are heterodimeric cell surface receptors, composed of an α- and a β-subunit, which mediate cell-extracellular matrix (ECM) interactions. Integrins mediate intracellular signals in response to extracellular stimuli, and cooperate with growth factor and other cytokine receptors. Cells execute their differentiated functions anchored to an ECM. In this thesis functional properties of the two collagen-binding integrins α2β1 and α11β1 were studied. In addition, the impact of β1 cytoplasmic tyrosines in collagen-induced signalling was analyzed.

The integrin α11β1 is the latest identified collagen-binding integrin. In this study, tissue distribution of α11 mRNA and protein during embryonal development was explored, and the first α11β1-mediated cellular functions were established. Both α11 protein and mRNA were present in mesenchymal cells in intervertebral discs and around the cartilage of the developing skeleton. α11 protein was also detected in cornea keratinocytes. α11β1 mediated cation-dependent adhesion to collagen types I and IV and localized to focal adhesions. In addition, α11β1 mediated contraction of a collagen lattice and supported cell migration through a collagen substrate. PDGF-BB and FBS both stimulated α11β1-mediated contraction and directed migration.

Expression of β1Y783,795F in β1-null cells, prevents activation of FAK in response to fibronectin, and decreases cell migration. In this study, we investigated how this mutation affected α2β1-mediated functions in response to collagen. The β1 mutation impaired collagen gel contraction and prevented activation of FAK, Cas and Src on planar collagen, but not in collagen gels. PDGF-BB stimulated contraction via αvβ3, which also induced activation of Cas in collagen gels. The YY-FF mutation also abolished β1A-dependent downregulation of β3.

In the final study integrin-crosstalk during collagen gel contraction was investigated. In cells lacking collagen-binding integrins αvβ3 mediated contraction. Clustering of β1-integrins by antibodies and PDGF-BB stimulated αvβ3-mediated contraction in an ERK-dependent way. Expression of α2β1, but not α11β1, prevented αvβ3-mediated contraction. Contraction by α2β1 and α11β1 was ERK-independent.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2003. 97 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1295
Cell and molecular biology, Cell- och molekylärbiologi
National Category
Biochemistry and Molecular Biology
urn:nbn:se:uu:diva-3686 (URN)91-554-5769-X (ISBN)
Public defence
2003-11-21, C10:301, BMC, Uppsala, 13:15
Available from: 2003-10-30 Created: 2003-10-30Bibliographically approved

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