ANGPTL3 stimulates endothelial cell adhesion and migration via integrin αvβ3 and induces blood vessel formation in vivo
Research output: Contribution to journal › Research article › Contributed › peer-review
Contributors
Abstract
The angiopoietin family of secreted factors is functionally defined by the C-terminal fibrinogen (FBN)-like domain, which mediates binding to the Tie2 receptor and thereby facilitates a cascade of events ultimately regulating blood vessel formation. By screening expressed sequence tag data bases for homologies to a consensus FBN-like motive, we have identified ANGPTL3, a liver-specific, secreted factor consisting of an N-terminal coiled-coil domain and the C-terminal FBN-like domain. Co-immunoprecipitation experiments, however, failed to detect binding of ANGPTL3 to the Tie2 receptor. A molecular model of the FBN-like domain of ANGPTL3 was generated and predicted potential binding to integrins. This hypothesis was experimentally confirmed by the finding that recombinant ANGPTL3 bound to alpha(v)beta(3) and induced integrin alpha(v)beta(3)-dependent haptotactic endothelial cell adhesion and migration and stimulated signal transduction pathways characteristic for integrin activation, including phosphorylation of Akt, mitogen-activated protein kinase, and focal adhesion kinase. When tested in the rat corneal assay, ANGPTL3 strongly induced angiogenesis with comparable magnitude as observed for vascular endothelial growth factor-A. Moreover, the C-terminal FBN-like domain alone was sufficient to induce endothelial cell adhesion and in vivo angiogenesis. Taken together, our data demonstrate that ANGPTL3 is the first member of the angiopoietin-like family of secreted factors binding to integrin alpha(v)beta(3) and suggest a possible role in the regulation of angiogenesis.
Details
Original language | English |
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Pages (from-to) | 17281-17290 |
Number of pages | 10 |
Journal | The Journal of biological chemistry |
Volume | 277 |
Issue number | 19 |
Publication status | Published - 10 May 2002 |
Peer-reviewed | Yes |
Externally published | Yes |
External IDs
Scopus | 0037053389 |
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Keywords
Keywords
- Amino Acid Sequence, Angiopoietin-2, Angiopoietin-Like Protein 3, Angiopoietin-like Proteins, Angiopoietins, Animals, Cell Adhesion, Cell Line, Cell Movement, Cells, Cultured, Cloning, Molecular, Cornea/metabolism, Endothelium/cytology, Fibrinogen/metabolism, Focal Adhesion Kinase 1, Focal Adhesion Protein-Tyrosine Kinases, Growth Substances/metabolism, Humans, Intercellular Signaling Peptides and Proteins, MAP Kinase Signaling System, Mice, Molecular Sequence Data, Neovascularization, Physiologic, Precipitin Tests, Protein Binding, Protein Structure, Tertiary, Protein-Tyrosine Kinases/metabolism, Proteins/metabolism, Rats, Receptors, Vitronectin/metabolism, Recombinant Proteins/metabolism, Sequence Homology, Amino Acid, Transfection