Collagen-binding integrin α2β1 activity in vivo and in vitro: Effects of platelet-derived growth factor-BB
1998 (English)Doctoral thesis, comprehensive summary (Other academic)
The expression of integrins by two cell clones from a rat colon carcinoma was investigated. Cloned cells that gave rise to regressive tumors, but not cells that gave rise to progressive, lethal, tumors, adhered to interstitial collagens through the integrin α2β1, although both cell types expressed it. These data suggest that the apparent activity of α2β1 is important for tumorinvasiveness.
Inhibition of the α2β1 integrin in rat paw skin lead to a lowering of the interstitial fluid pressure (PIF). an effect that could be overcome by platelet-derived growth factor-BB (PDGF-BB).
PDGF-BB could stimulate the synthesis of the α2, but not α1, α3 or β1 integrin chains in human AG1518 fibroblasts.
PDGF-BB also stimulated cell spreading and induced a rapid and transientrelocalization of α2β1 in AG1518 fibroblasts. The relocalization was dependent on phosphatidylinositol 3-kinase (PI3-K) and protein kinase C (PKC), and involved disassembly of focal adhesions as seen in interference reflection microscopy (IRM). The mobility of β1-integrins in the cell membrane was increased in cells stimulated with PDGF-BB.
PDGF-BB-stimulated collagen gel contraction, as well as the induction of a rise in cytoplasmic free calcium [Ca2+]i were shown to depend on PI3-K. The experimental anti-inflamatory drug α-trinositol induced an increase in [Ca2+]i and could restore PI3-K-dependent chemotaxis towards PDGF-BB as well as the lowering of PIF induced bv inhibitors of PI3K.
In conclusion: α2β1 is implicated in invasiveness of tumor cells in vivo, and in the maintenance of interstitial fluid pressure (PIF). PDGF-BB is shown to regulate PIF, to stimulate synthesis of the integrin α2 chain, and to modulate cytoskeletal interactions of α1- integrins. The maintenance of PIF, as well as PDGF-BB-stimulation of collagen gel contraction, induction of integrin reorganization from focal adhesions, and induction of a calcium response, was dependent on an activation of PI3-K. PI3-K is hypothesized to mediate these effects at least in part through induction of a rise in [Ca2+]i.
Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 1998. , 53 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 739
Biochemistry, Integrin α2β1, PDGF-BB, fibroblast, interstitial fluid pressure, cytoskeletal interaction, phosphatidylinositol 3-kinase, [Ca2+]i
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject Medical and Physiological Chemistry
IdentifiersURN: urn:nbn:se:uu:diva-1222ISBN: 91-554-4136-XOAI: oai:DiVA.org:uu-1222DiVA: diva2:160780
1998-03-13, room B41, Biomedical Center, Uppsala University, Uppsala, 09:15