title: CRSBP-1/LYVE-1 ligands disrupt lymphatic intercellular adhesion by inducing tyrosine phosphorylation and internalization of VE-cadherin.
abstract: Cell-surface retention sequence (CRS) binding protein (CRSBP-1) is a membrane glycoprotein identified by its ability to bind PDGF-BB and VEGF-A via their CRS motifs (clusters of basic amino acid residues). CRSBP-1 is identical to LYVE-1 and exhibits dual ligand (CRS-containing proteins and hyaluronic acid) binding activity, suggesting the importance of CRSBP-1 ligands in lymphatic function. Here, we show that CRSBP-1 ligands induce disruption of VE-cadherin-mediated intercellular adhesion and opening of intercellular junctions in lymphatic endothelial cell (LEC) monolayers as determined by immunofluorescence microscopy and Transwell permeability assay. This occurs by interaction with CRSBP-1 in the CRSBP-1-PDGFβR-β-catenin complex, resulting in tyrosine phosphorylation of the complex, dissociation of β-catenin and p120-catenin from VE-cadherin, and internalization of VE-cadherin. Pretreatment of LECs with a PDGFβR kinase inhibitor abolishes ligand-stimulated tyrosine phosphorylation of VE-cadherin, halts the ligand-induced disruption of VE-cadherin intercellular adhesion and blocks the ligand-induced opening of intercellular junctions. These CRSBP-1 ligands also induce opening of lymphatic intercellular junctions that respond to PDGFβR kinase inhibitor in wild-type mice (but not in Crsbp1-null mice) as evidenced by increased transit of injected FITC-dextran and induced edema fluid from the interstitial space into lymphatic vessels. These results disclose a novel mechanism involved in the opening of lymphatic intercellular junctions.
authors: Departments of Biochemistry and Molecular Biology, St Louis University School of Medicine, Doisy Research Center, 1100 S. Grand Boulevard, St Louis, MO 63104, USA.
authors: Wei-Hsien
authors: WH
authors: Hou
authors: I-Hua
authors: IH
authors: Liu
authors: Cheng C
authors: CC
authors: Tsai
authors: Frank E
authors: FE
authors: Johnson
authors: Shuan Shian
authors: SS
authors: Huang
authors: Jung San
authors: JS
authors: Huang
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion; D002460:Cell Line; D042783:Endothelial Cells / Q000502:physiology*; D006820:Hyaluronic Acid / Q000378:metabolism; D008024:Ligands; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D011485:Protein Binding; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D006820:Hyaluronic Acid; D008024:Ligands; D008565:Membrane Proteins; D020797:Receptor, Platelet-Derived Growth Factor beta; D014443:Tyrosine; D051176:beta Catenin; D000099152:Cadherin 5; C091632:cell-surface retention-binding protein 1