title: A monoclonal antibody against CD148, a receptor-like tyrosine phosphatase, inhibits endothelial-cell growth and angiogenesis.
abstract: Angiogenesis contributes to a wide range of neoplastic, ischemic, and inflammatory disorders. Definition of the intrinsic molecular controls in angiogenic vessel growth promises novel therapeutic approaches for angiogenesis-related diseases. CD148 (also named DEP-1/PTP eta) is a receptor-like protein tyrosine phosphatase that is abundantly expressed in vascular endothelial cells. To explore a role of CD148 in endothelial vessel formation, we generated a monoclonal antibody, Ab1, against the ectodomain sequence of CD148 and examined its effects on endothelial-cell growth and vessel formation. Here we report that a bivalent, but not a monovalent, form of the Ab1 antibody inhibits endothelial-cell growth and blocks angiogenesis in mouse cornea in vivo. We further demonstrate that (1) bivalent Ab1 arrests cell-cycle progression of CD148-transfected CHO cells at G(0)/G(1) phase, (2) coexpression of catalytically inactive CD148 mutants attenuates the Ab1-cell growth inhibition, and (3) bivalent Ab1 suppresses phosphorylation of ERK1/2 kinases and Met tyrosine kinase as activated CD148 does, with an increase in CD148-associated tyrosine phosphatase activity. Taken together, these findings demonstrate that Ab1-induced ectodomain oligomerization arrests endothelial-cell growth through catalytic activity of the CD148 cytoplasmic domain. The present study defines CD148 as a valuable molecular target for antiangiogenesis therapy.
authors.affiliation: Vanderbilt University Medical Center, Division of Nephrology, Nashville, TN 37232, USA. takamune.takahashi@vanderbilt.edu
authors.forename: Takamune
authors.initials: T
authors.lastname: Takahashi
authors.forename: Keiko
authors.initials: K
authors.lastname: Takahashi
authors.forename: Raymond L
authors.initials: RL
authors.lastname: Mernaugh
authors.forename: Nobuo
authors.initials: N
authors.lastname: Tsuboi
authors.forename: Hua
authors.initials: H
authors.lastname: Liu
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Daniel
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D016466:CHO Cells; D003315:Cornea / Q000098:blood supply / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006224:Cricetinae; D003412:Cricetulus; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000276:immunology / Q000494:pharmacology*; D016193:G1 Phase / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D017434:Protein Structure, Tertiary / Q000235:genetics; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3; D016192:Resting Phase, Cell Cycle / Q000187:drug effects / Q000235:genetics / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D004791:Enzyme Inhibitors; D019859:Proto-Oncogene Proteins c-met; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C486288:PTPRJ protein, human; D017027:Protein Tyrosine Phosphatases; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3