PLEIOTROPHIN SIGNALING MECHANISMS

Pleiotroin(PTN)是PDGF诱导基因的17kD产物，是 对损伤的反应上调，其产品促进生长， 分化和血管生成。PTN基因也是原癌基因， PTN转化的细胞在裸鼠体内形成高度血管性肿瘤。 然而，PTN信号细胞的机制尚不清楚。我们最近 建立PTN与受体蛋白酪氨酸磷酸酶的结合 PTN中(RPTP)β/Zeta相关蛋白和信号分子β-catenin 刺激细胞，PTN刺激的细胞增加了酪氨酸 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。我们会 PTN与RPTPbeta/Zeta的结合及其对 RPTPbeta/Zeta磷酸酶活性，确定RPTPbeta/Zeta在 依赖PTN转化的恶性细胞，并建立 RPTPbeta/Zeta通过异源二聚体的“激活” PTN胞外结构域在内皮细胞中的作用 和少突胶质祖细胞。我们还将寻求生理学上的 RPTPbeta/Zeta的底物，试图建立β-连环蛋白是一种 RPTPbeta/Zeta底物，并鉴定PDZ结构域包含 与极端C-末端相互作用的细胞内蛋白质 RPTPbeta/Zeta建立细胞内蛋白质复合体。这些 实验将证实PTN与RPTPβ/Zeta和 确定依赖PTN的细胞反应是通过 RPTPbeta/Zeta。结果将确定下游信号换能器 PTN发信号并确定它们可能如何发挥作用。 这些实验的结果可能会促进对PTN的理解 正常的PTN依赖功能反应中的信号通路， 包括血管生成和恶性肿瘤的病理反应 转型。这些结果可能确定治疗的部位 干预以干扰疾病中不适当的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.