BAG3 AS A REGULATOR OF CELL MOTILITY

描述(由申请人提供)： BAG3结合并调节Hsp70功能(Takayama等人)。生物化学杂志274：781,1999)。BAG3蛋白含有一个WW结构域和一个带有SH3结合基序的富含Pro的区域，提示它可能与膜下信号转导相关的蛋白相互作用，募集Hsp70形成信号复合体，改变细胞的反应。除了70 kDa的热休克蛋白外，BAG3还可与多种细胞蛋白结合，包括GDP交换因子和含SH3的信号转导蛋白。BAG3在Balb/c 3T3成纤维细胞中过表达可诱导转化，BAG3在人类肿瘤，尤其是胰腺癌中也有过表达。因此，我们推测BAG3代表一种新的原癌基因，它可能影响细胞转化、锚定非依赖性生长或其他与恶性表型相关的过程。我们还发现BAG3过表达增加了Cos7细胞的运动能力。此外，bag3纯合子缺陷的小鼠胚胎成纤维细胞表现出肌动蛋白细胞骨架的失调和运动异常。对BAG3蛋白的分子机制进行了实验研究。(1)研究BAG3是如何控制细胞骨架的，并确定BAG3的哪些结构域是必需的；(2)探索BAG3与环境基金、SH3蛋白和Hsp70蛋白相互作用的功能意义；(3)探讨BAG3在肿瘤中的表达及其在恶性转化中的作用。这些研究将提供对BAG3致癌特性的见解，并可能有助于寻找癌症治疗的新靶点。

DESCRIPTION (provided by applicant): BAG3 binds to and regulates Hsp70 function (Takayama, et al. J Biol Chem 274: 781, 1999). The BAG3 protein contains a WW domain and a proline-rich region with SH3-binding motifs, suggesting that it may interact with proteins relevant to submembranous signal transduction, recruiting Hsp70 to signaling complexes and altering cell responses. BAG3 binds to several cellular proteins including a GDP Exchange Factor (GEF) and SH3-containing signal transducing proteins, in addition to 70-kDa heat shock proteins. BAG3 over-expression in Balb/c 3T3 fibroblasts induces transformation and BAG3 over-expression has been observed in human cancers, especially pancreatic cancer. We speculate therefore that BAG3 represents a novel proto-oncogene that may affect cell transformation, anchorage-independent growth, or other processes relevant to the malignant phenotype. Also we have found that BAG3 over-expression increases motility of Cos7 cell. Moreover, homozygous bag3 deficient mouse embryonic fibroblasts exhibit dysregulation of actin cytoskeleton and abnormal motility. Experiments are proposed to explore the molecular mechanism of the BAG3 protein. (1) Investigating how BAG3 controls cytoskeleton and determining what domains of BAG3 are required including; (2) Exploring the functional significance of interactions of BAG3 with GEF, SH3 proteins and Hsp70 proteins; and (3) Exploring BAG3 expression in cancer and its role in malignant transformation. These studies will provide insights into the oncogenic properties of BAG3 and may assist in finding new targets for cancer therapy.