Betaglycan as a modulator of TGF-b signaling in hepatoma

描述（由申请人提供）：转化生长因子（TGF）-β通过一种简单但具有复杂性和在许多水平上调节潜力的途径发出信号。TGF-β信号传导的改变在癌症和转移中起重要作用。这在肝脏中尤其如此，肝脏需要精确调节TGF-β信号以维持正常组织的稳态。一种潜在的重要但知之甚少的TGF-β信号调节剂是β聚糖，也称为III型TGF-β受体。β聚糖是TGF-β的辅助受体，其具有全长膜锚定形式和蛋白水解裂解的可溶形式。β聚糖的功能传统上被理解为增强TGF-β信号传导。初步数据表明，它也是一种抑制性受体，其糖胺聚糖修饰在确定其功能中起重要作用。额外的初步数据表明，β聚糖的可溶性形式以及胞外域切割后剩余的膜锚定胞质结构域以高水平存在，并且是TGF-β信号传导的潜在重要调节剂。 该提议的中心假设是β聚糖通过其全长形式和两种蛋白水解切割形式起作用，是正常和恶性细胞中TGF-β信号传导的重要调节剂。使用培养的人肝癌细胞作为模型系统，我们提出了一系列实验来证明β聚糖调节TGF-β信号传导并确定其作用机制。具体而言，我们建议： 1.表征β聚糖和两种丝氨酸-苏氨酸激酶受体之间的相互作用，并确定β聚糖如何介导激酶受体之间的相互作用; 2.确定可溶性受体的调节和功能; 3.确定跨膜/胞质蛋白的功能。 这些创新的方法将为TGF-β信号在肝细胞增殖和恶性转化中的重要作用提供新的机制见解。它们也将大大增加我们对TGF-β信号传导的理解，并为β聚糖的体内研究铺平道路。

DESCRIPTION (provided by applicant): Transforming Growth Factor (TGF)-beta signals through a pathway that is simple yet has the potential for complexity and modulation at many levels. Alterations in TGF-beta signaling play an important role in cancer and metastasis. This is particularly true in the liver, which requires exquisite regulation of TGF-beta signaling for the maintenance of normal tissue homeostasis. One potentially important but poorly understood modulator of TGF-beta signaling is betaglycan, also known as the type III TGF-beta receptor. Betaglycan is an accessory receptor for TGF-beta that has both a full-length, membrane-anchored form and a proteolytically-cleaved soluble form. The function of betaglycan has traditionally been understood to be enhancement of TGF-beta signaling. Preliminary data demonstrate that it is also an inhibitory receptor, and that its glycosaminoglycan modifications play an important role in determining its function. Additional preliminary data suggests that the soluble form of betaglycan, as well as the membrane-anchored cytoplasmic domain remaining after cleavage of the ectodomain, are present at high levels and are potentially important regulators of TGF-beta signaling. The central hypothesis of this proposal is that betaglycan, acting through its full-length form and both proteolytically cleaved forms, is an important modulator of TGF-beta signaling in normal and malignant cells. Using human hepatoma cells in culture as a model system, we propose a series of experiments to demonstrate that betaglycan regulates TGF-beta signaling and to determine its mechanisms of action. Specifically, we propose to: 1. Characterize the interactions between betaglycan and the two serine-threonine kinase receptors, and determine how betaglycan mediates interactions between the kinase receptors; 2. Determine the regulation and function of the soluble receptor; 3. Determine the function of the transmembrane/cytoplasmic protein. These innovative approaches will provide new mechanistic insight into the important role of TGF-beta signaling in hepatocyte proliferation and malignant transformation. They will also greatly increase our understanding of TGF-beta signaling in general, and will pave the way for in vivo studies of beta glycan.