PLEIOTROPHIN SIGNALING MECHANISMS

多效生长因子（PTN）是PDGF诱导基因的17 kD产物， 在受伤时上调，其产物促进生长， 分化和血管生成。 Ptn基因也是原癌基因， Ptn转化细胞在裸鼠体内形成高度血管化的肿瘤。 然而，PTN信号细胞的机制尚不清楚。我们最近 建立了PTN与受体蛋白酪氨酸磷酸酶结合 PTN中的（RPTP）beta/zeta缔合物和信号分子β-连环蛋白 PTN刺激的细胞，并且PTN刺激的细胞具有增加的酪氨酸 β-连环蛋白的磷酸化。 我们现在建议研究和表征PTN/RTPbeta/zeta相互作用 并确定其在生长和分化中的意义。我们将 表征PTN与RPTPbeta/zeta的结合及其对 RPTP β/ζ磷酸酶活性，确定RPTP β/ζ在 恶性细胞依赖PTN进行转化，并建立 RPTP β/zeta通过异源性 细胞外结构域概括了PTN在内皮细胞中的作用 和少突胶质细胞祖细胞。我们还将寻求生理上的 RPTP β/ζ的底物，试图建立β-连环蛋白是一个 RPTP β/ζ底物，并鉴定含有PDZ结构域 细胞内的蛋白质与极端的C-末端相互作用， RPTP β/zeta以建立细胞内蛋白质复合物。这些 实验将证实PTN与RPTP β/ζ的关系， 确定PTN依赖性细胞应答是通过 RPTP β/ζ。结果将确定下游信号传感器 PTN发信号并确定它们如何工作。 这些实验的结果可能会促进对PTN的理解 在正常PTN依赖性功能反应中的信号传导途径， 包括血管生成和恶性肿瘤的病理反应， 转型这些结果可以确定治疗的部位 干预破坏疾病中不适当的PTN信号。

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.