Cell adhesion to fibrillin-1 molecules and microfibrils is mediated by alpha 5 beta 1 and alpha v beta 3 integrins.
Fibrillins are the major glycoprotein components of microfibrils that form a template for tropoelastin during elastic fibrillogenesis. We have examined cell adhesion to assembled purified microfibrils, and its molecular basis. Human dermal fibroblasts exhibited Arg-Gly-Asp and cation-dependent adhesion to microfibrils and recombinant fibrillin-1 protein fragments. Strong integrin alpha 5 beta 1 interactions with fibrillin ligands were identified, but integrin alpha v beta 3 also contributed to cell adhesion. Fluorescence-activated cell sorting analysis confirmed the presence of abundant alpha 5 beta 1 and some alpha v beta 3 receptors on these cells. Adhesion to microfibrils and to Arg-Gly-Asp containing fibrillin-1 protein fragments induced signaling events that led to cell spreading, altered cytoskeletal organization, and enhanced extracellular fibrillin-1 deposition. Differences in cell shape when plated on fibrillin or fibronectin implied substrate-specific alpha 5 beta 1-mediated cellular responses. An Arg-Gly-Asp-independent cell adhesion sequence was also identified within fibrillin-1. Adhesion and spreading of smooth muscle cells on fibrillin ligands was enhanced by antibody-induced beta1 integrin activation. A375-SM melanoma cells bound Arg-Gly-Asp-containing fibrillin-1 protein fragments mainly through alpha v beta 3, whereas HT1080 cells used mainly alpha 5 beta 1. This study has shown that fibrillin microfibrils mediate cell adhesion, that alpha 5 beta 1 and alpha v beta 3 are both important but cell-specific fibrillin-1 receptors, and that cellular interactions with fibrillin-1 influence cell behavior.
Bax
Daniel V
DV
United Kingdom Centre for Tissue Engineering, School of Biological Sciences, University of Manchester, United Kingdom.
Bernard
Sarah E
SE
Lomas
Amanda
A
Morgan
Amanda
A
Humphries
Jon
J
Shuttleworth
C Adrian
CA
Humphries
Martin J
MJ
Kielty
Cay M
CM
D000906:Antibodies / Q000737:chemistry; D002412:Cations; D002448:Cell Adhesion; D002469:Cell Separation; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D005091:Exons; D000071838:Fibrillin-1; D000071837:Fibrillins; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D039081:Integrin alpha5beta1 / Q000378:metabolism*; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism; D008024:Ligands; D020894:Microfibrils / Q000378:metabolism*; D008840:Microfilament Proteins / Q000737:chemistry* / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D009130:Muscle, Smooth / Q000166:cytology; D010641:Phenotype; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D054392:Adipokines
D000906:Antibodies; D002412:Cations; D000071838:Fibrillin-1; D000071837:Fibrillins; D039081:Integrin alpha5beta1; D039302:Integrin alphaVbeta3; D016023:Integrins; D008024:Ligands; D008840:Microfilament Proteins; D011994:Recombinant Proteins; C000605722:FBN1 protein, human; D054392:Adipokines