Betaglycan as a modulator of TGF-b signaling in hepatoma

描述(申请人提供)：转化生长因子(转化生长因子)-β信号通过一种简单的途径，但具有在许多水平上的复杂性和调节的潜力。转化生长因子-β信号的改变在肿瘤和转移中起着重要作用。这在肝脏尤其如此，它需要对转化生长因子-β信号的精细调控，以维持正常的组织动态平衡。β-聚糖是一种潜在的重要但知之甚少的转化生长因子-β信号调节剂，也被称为III型转化生长因子-β受体。Betaglycan是转化生长因子-β的辅助受体，既有全长的膜锚定形式，也有蛋白水解性裂解的可溶性形式。传统上，β-聚糖的功能被理解为增强转化生长因子-β信号转导。初步数据表明，它也是一种抑制性受体，其糖胺多糖的修饰在决定其功能方面发挥着重要作用。更多的初步数据表明，β-葡聚糖的可溶性形式，以及胞外结构域被切割后残留的膜锚定的细胞质结构域，存在于高水平，并可能是转化生长因子-β信号的重要调节因子。 这一建议的中心假设是，在正常和恶性细胞中，β-聚糖通过其全长形式和两种蛋白水解性裂解形式发挥作用，是转化生长因子-β信号的重要调节器。以培养的人肝癌细胞为模型系统，我们提出了一系列实验，以证明β-聚糖对转化生长因子-β信号的调节作用，并确定其作用机制。具体来说，我们建议： 1.研究β-多糖与两种丝氨酸-苏氨酸激酶受体之间的相互作用，并确定β-聚糖如何介导这两种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。 这些创新的方法将提供新的机制洞察转化生长因子-β信号在肝细胞增殖和恶性转化中的重要作用。它们还将极大地增加我们对转化生长因子-β信号的理解，并将为体内研究β-葡聚糖铺平道路。

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.