A monoclonal antibody against CD148, a receptor-like tyrosine phosphatase, inhibits endothelial-cell growth and angiogenesis.

Takahashi T, Takahashi K, Mernaugh RL, Tsuboi N, Liu H, Daniel TO
Blood. 2006 108 (4): 1234-42

PMID: 16597593 · PMCID: PMC1895872 · DOI:10.1182/blood-2005-10-4296

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.

MeSH Terms (22)

Animals Antibodies, Monoclonal CHO Cells Cornea Cricetinae Cricetulus Endothelial Cells Enzyme Inhibitors G1 Phase Humans Inflammation Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Neoplasms Neovascularization, Pathologic Phosphorylation Protein Processing, Post-Translational Protein Structure, Tertiary Protein Tyrosine Phosphatases Proto-Oncogene Proteins c-met Receptor-Like Protein Tyrosine Phosphatases, Class 3 Resting Phase, Cell Cycle

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