TYROSINE PHOSPHATASES IN ENDOTHELIAL GROWTH CONTROL

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Definition of the intrinsic molecular controls that regulate angiogenic and vasculogenic blood vessel growth promises to provide targets for therapy of solid tumors, diabetic retinopathy, arthritis, skin and other diseases. Developmental assembly, remodeling and maintenance of microvascular integrity are dynamic processes regulated by endothelial responses to local environmental cues, transduced through surface receptors. One of the properties fundamental to endothelium in mature vessels is cell context dependent constraints over proliferation. We have advanced the hypothesis that an endothelial receptor tyrosine phosphatase, ECRTP/CD148, transduces cell growth arrest signals on juxtacrine contact with a counter-receptor. A monoclonal antibody, ECRTP.ab1, that specifically binds ECRTP/CD148 ectodomain sequences localizes its expression to endothelium of arteries and capillaries in kidney, and other tissues. Endothelial progenitor cells express ECRTP/CD148 prior to their incorporation into developing glomerular capillaries of kidney, and ECRTP/CD148 accumulates at inter-endothelial points of contact. Bivalent forms of ECRTP.ab1 block cultured endothelial cell proliferation and migration, inhibit angiogenesis in a mouse corneal assay, and promote dephosphorylation of intracellular tyrosine phosphoproteins. Expression of ECRTP/CD148 in deficient cell lines confers antibody-induced growth inhibition that is dependent upon intrinsic tyrosine phosphatase activity. The current proposal describes plans to: 1) define a functional counter-receptor to CD148, 2) to identify intracellular substrates of ECRTP/CD148 and their role in endothelial growth arrest, and 3) to define ECRTP/CD148 function during vascular development. Homologous recombinant ES lines and mice will define function of ECRTP/CD148 in developmental vascular assembly. These studies will extend definition of molecular controls regulating angiogenesis, and will define new molecular targets for anti-angiogenic therapies.