PLEIOTROPHIN SIGNALING MECHANISMS

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Pleiotrophin (PTN) is the 17 kD product of a PDGF inducible gene that is up-regulated in response to injury and whose product promotes growth, differentiation and angiogenesis. The Ptn gene also is proto-oncogene and Ptn transformed cells develop highly vascular tumors in the nude mouse. However, the mechanisms by which PTN signal cells are unknown. We recently established the PTN binds to the Receptor Protein Tyrosine Phosphatase (RPTP) beta/zeta associates and the signaling molecule beta-catenin in PTN stimulated cells, and that PTN stimulated cells have increased tyrosine phosphorylation of beta-catenin. We now propose to study and characterize the PTN/RTPbeta/zeta interaction and to establish its significance in growth and differentiation. We will characterize the binding of PTN to RPTPbeta/zeta and its effect on RPTPbeta/zeta phosphatase activity, establish the role of RPTPbeta/zeta in malignant cells that depend upon PTN for transformation, and establish that "activation" of RPTPbeta/zeta through dimerization of a heterologous extracellular domain recapitulates the effects of PTN in endothelial cells and oligodendrocyte progenitors. We will also seek the physiological substrates for RPTPbeta/zeta, attempt to establish the beta-catenin is a substrate for RPTPbeta/zeta, and identify PDZ domain containing intracellular proteins that interact with the extreme C-terminal of RPTPbeta/zeta to establish intracellular protein complexes. These experiments will confirm the relationship of PTN to RPTPbeta/zeta and establish that PTN dependent cellular responses are mediated through RPTPbeta/zeta. The results will identify downstream signal transducers of the PTN signal and establish how they may function. The results of these experiments may advance understanding of the PTN signaling pathway in both normal PTN dependent functional responses, including angiogenesis and the pathological responses of malignant transformation. These results may identify sites for therapeutic intervention to disrupt inappropriate PTN signals in diseases.