title: Dentin matrix protein 1 induces membrane expression of VE-cadherin on endothelial cells and inhibits VEGF-induced angiogenesis by blocking VEGFR-2 phosphorylation.
abstract: Dentin matrix protein 1 (DMP1) is a member of the small integrin-binding ligand N-linked glycoprotein (SIBLING) family, a group of proteins initially described as mineralized extracellular matrices components. More recently, SIBLINGs have been implicated in several key steps of cancer progression, including angiogenesis. Although proangiogenic activities have been demonstrated for 2 SIBLINGs, the role of DMP1 in angiogenesis has not yet been addressed. We demonstrate that this extracellular matrix protein induced the expression of vascular endothelial cadherin (VE-cadherin), a key regulator of intercellular junctions and contact inhibition of growth of endothelial cells that is also known to modulate vascular endothelial growth factor receptor 2 (VEGFR-2) activity, the major high-affinity receptor for VEGF. DMP1 induced VE-cadherin and p27(Kip1) expression followed by cell-cycle arrest in human umbilical vein endothelial cells (HUVECs) in a CD44-dependent manner. VEGF-induced proliferation, migration, and tubulogenesis responses were specifically blocked on DMP1 pretreatment of HUVECs. Indeed, after VE-cadherin induction, DMP1 inhibited VEGFR-2 phosphorylation and Src-mediated signaling. However, DMP1 did not interfere with basic fibroblast growth factor-induced angiogenesis. In vivo, DMP1 significantly reduced laser-induced choroidal neovascularization lesions and tumor-associated angiogenesis. These data enable us to put DMP1 on the angiogenic chessboard for the first time and to identify this protein as a new specific inhibitor of VEGF-induced angiogenesis.
authors.affiliation: Metastasis Research Laboratory, Grappe Disciplinaire de Génoprotéomique Appliquée (GIGA)–Cancer, Liège, Belgium.
authors.forename: Sophie
authors.initials: S
authors.lastname: Pirotte
authors.forename: Virginie
authors.initials: V
authors.lastname: Lamour
authors.forename: Vincent
authors.initials: V
authors.lastname: Lambert
authors.forename: Maria-Luz
authors.initials: ML
authors.lastname: Alvarez Gonzalez
authors.forename: Sandra
authors.initials: S
authors.lastname: Ormenese
authors.forename: Agnès
authors.initials: A
authors.lastname: Noël
authors.forename: Denis
authors.initials: D
authors.lastname: Mottet
authors.forename: Vincent
authors.initials: V
authors.lastname: Castronovo
authors.forename: Akeila
authors.initials: A
authors.lastname: Bellahcène
mesh_terms: D043925:Angiogenesis Inducing Agents; D015703:Antigens, CD / Q000096:biosynthesis*; D015820:Cadherins / Q000096:biosynthesis*; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000502:physiology*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006801:Humans; D009389:Neovascularization, Pathologic; D010750:Phosphoproteins / Q000502:physiology*; D010766:Phosphorylation; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*; D042442:Vascular Endothelial Growth Factors / Q000494:pharmacology*; D000099152:Cadherin 5
chemical_list: D043925:Angiogenesis Inducing Agents; D015703:Antigens, CD; D015820:Cadherins; D016326:Extracellular Matrix Proteins; D016222:Fibroblast Growth Factor 2; D010750:Phosphoproteins; D040301:Vascular Endothelial Growth Factor Receptor-2; D042442:Vascular Endothelial Growth Factors; D000099152:Cadherin 5; C513309:DMP1 protein, human