BAG3 AS A REGULATOR OF CELL MOTILITY

描述（由申请人提供）： BAG 3与Hsp 70结合并调节其功能（Takayama等，J Biol Chem 274：781，1999）。BAG 3蛋白含有WW结构域和富含脯氨酸的区域，该区域具有SH 3结合基序，这表明它可能与膜下信号转导相关的蛋白质相互作用，将Hsp 70募集到信号复合物中并改变细胞反应。除了70 kDa热休克蛋白之外，BAG 3还与多种细胞蛋白质结合，包括GDP交换因子（GEF）和含SH 3的信号传导蛋白。BAG 3在Balb/c 3 T3成纤维细胞中的过表达诱导转化，并且已经在人类癌症，特别是胰腺癌中观察到BAG 3过表达。因此，我们推测BAG 3代表一种新的原癌基因，可能会影响细胞转化，锚定非依赖性生长，或其他相关的恶性表型的过程。我们还发现BAG 3过表达增加了Cos 7细胞的运动性。此外，纯合子bag 3缺陷小鼠胚胎成纤维细胞表现出肌动蛋白细胞骨架和异常运动失调。实验拟探讨BAG 3蛋白的分子机制。(1)研究BAG 3如何控制细胞骨架并确定需要BAG 3的哪些结构域，包括：（2）探索BAG 3与GEF，SH 3蛋白和Hsp 70蛋白相互作用的功能意义;（3）探索BAG 3在癌症中的表达及其在恶性转化中的作用。这些研究将为BAG 3的致癌特性提供见解，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.