title: ANGPTL3 stimulates endothelial cell adhesion and migration via integrin alpha vbeta 3 and induces blood vessel formation in vivo.
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.
authors.affiliation: Department of Molecular Oncology, Genentech, Inc., South San Francisco, California 94080, USA.
authors.forename: Gieri
authors.initials: G
authors.lastname: Camenisch
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Pisabarro
authors.forename: Daniel
authors.initials: D
authors.lastname: Sherman
authors.forename: Joe
authors.initials: J
authors.lastname: Kowalski
authors.forename: Mark
authors.initials: M
authors.lastname: Nagel
authors.forename: Phil
authors.initials: P
authors.lastname: Hass
authors.forename: Ming-Hong
authors.initials: MH
authors.lastname: Xie
authors.forename: Austin
authors.initials: A
authors.lastname: Gurney
authors.forename: Sarah
authors.initials: S
authors.lastname: Bodary
authors.forename: Xiao Huan
authors.initials: XH
authors.lastname: Liang
authors.forename: Kevin
authors.initials: K
authors.lastname: Clark
authors.forename: Maureen
authors.initials: M
authors.lastname: Beresini
authors.forename: Napoleone
authors.initials: N
authors.lastname: Ferrara
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Gerber
mesh_terms: D000595:Amino Acid Sequence; D042702:Angiopoietin-2; D000091303:Angiopoietin-Like Protein 3; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; D000818:Animals; D002448:Cell Adhesion; D002460:Cell Line; D002465:Cell Movement; D002478:Cells, Cultured; D003001:Cloning, Molecular; D003315:Cornea / Q000378:metabolism; D004727:Endothelium / Q000166:cytology*; D005340:Fibrinogen / Q000378:metabolism; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006133:Growth Substances / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D020935:MAP Kinase Signaling System; D051379:Mice; D008969:Molecular Sequence Data; D018919:Neovascularization, Physiologic; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D051381:Rats; D019030:Receptors, Vitronectin / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014162:Transfection
chemical_list: D042702:Angiopoietin-2; D000091303:Angiopoietin-Like Protein 3; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; C404495:Angptl3 protein, mouse; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D019030:Receptors, Vitronectin; D011994:Recombinant Proteins; D005340:Fibrinogen; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; C496051:Ptk2 protein, mouse; C496052:Ptk2 protein, rat