BAG3 AS A REGULATOR OF CELL MOTILITY

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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.