Tyrosine Phosphatases in Endothelial Growth Control

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DESCRIPTION (provided by applicant): Dysregulated capillary and arterial growth has a major impact on our health and contributes to numerous malignant, ischemic and inflammatory disorders. Definition of the intrinsic molecular controls that regulate angiogenic blood vessel growth promises novel therapeutic approaches for a variety of diseases including heart disease, diabetes and cancer. Although previous works have identified the endothelial receptors that induce vessel formation, little is known about the functional endothelial receptors that transduce "angiostatic" signals. We have advanced the hypothesis that receptor tyrosine phosphatases (RPTPs) signal endothelial growth arrest upon cell-cell contacts, through juxtacrine contact with counter-receptors. We have isolated a RPTP, CD148 (DEP-1/PTPq), from human renal microvascular endothelial cells and shown that: 1) CD148 is abundantly expressed in developing and mature vascular endothelium of various organs, 2) CD148 is accumulated at interendothelial sites and its activity increases with cell density, 3) the CD148 homozygous mutant mice die at mid-gestation due to vascularization failure accompanied by disordered endothelial vessel growth and endothelial cell proliferation, 4) a CD148 monoclonal antibody against the ectodomain sequence has a prominent anti-angiogenic activity to inhibit proliferation of culture endothelial cells and block angiogenesis in vivo, 5) CD148 interacts through the ectodomain (inter-molecular association) and forced CD148 dimerization inhibits cell proliferation, 6) CD148 constitutively associates with FGF receptor, and 7) CD148 cytoplasmic domain interacts with- and dephosphorylates the PI3 kinase p85 subunit and p120 catenin molecules. These findings suggest a pivotal role of CD148 to regulate endothelial cell growth upon cell-ceU contacts. To further define role of CD148 in blood vessel formation, the present proposal describes experimental approaches to: 1) map the extracellular subdomain responsible for mediating inter-molecular associations and elucidate its importance in regulation of CD148 activity and density-mediated endothelial growth arrest, 2) define biological importance of the molecular interaction between CDt48 and FGF receptor, p85, and p120 catenin in endothelial growth control, and 3) determine role of CD148 in endothelial vessel formation. These complementary efforts will identify a novel pathway that regulates endothelial cell growth through CD148 and promise new strategies for anti-angiogenesis therapy.