BAG3 regulates motility and adhesion of epithelial cancer cells.
BAG3 protein binds to and regulates Hsp70 chaperone activity. 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 signal transduction, recruiting Hsp70 to signaling complexes and altering cell responses. BAG3 overexpression has been observed in human cancers. We show here that homozygous BAG3-deficient mouse embryonic fibroblasts (MEF) exhibit delayed formation of filopodia and focal adhesion complexes when freshly plated. BAG3-deficient MEFs show reduced cell motility in culture. We observed that endogenous BAG3 protein is highly expressed in many human epithelial cancer cell lines, especially adenocarcinomas. Gene transfer-mediated overexpression of BAG3 increased motility of Cos7 cell and several human cancer cell lines, including breast cancer MCF7 and prostate cancer DU145 and ALVA31 cell lines. Conversely, reduction of BAG3 protein by RNA interference (RNAi) decreased cell motility in four of four epithelial tumor lines tested. We observed an influence of BAG3 on cell adhesion in culture. In Cos7 kidney epithelial cells, BAG3 protein partially colocalizes with actin at the leading edge of migrating cells, wherein active actin polymerization and nucleation occur. RNAi-mediated reductions in BAG3 expression were associated with decreased Rac1 activity, suggesting a role for BAG3 in regulating this small GTPase involved in actin-cytoskeleton dynamics. In mice, RNAi-mediated reductions in BAG3 in a human tumor xenograft suppressed invasion and metastasis in vivo. Thus, the high levels of BAG3 protein seen in some epithelial cancer cell lines may be relevant to mechanisms of tumor invasion and metastasis.
Iwasaki
Masahiro
M
Medical College of Georgia, Augusta, Georgia, USA.
Homma
Sachiko
S
Hishiya
Akinori
A
Dolezal
Samuel J
SJ
Reed
John C
JC
Takayama
Shinichi
S
D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis / Q000502:physiology*; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D019556:COS Cells; D002352:Carrier Proteins / Q000032:analysis / Q000737:chemistry / Q000502:physiology*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D002522:Chlorocebus aethiops; D018840:HSP70 Heat-Shock Proteins / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009375:Neoplasms, Glandular and Epithelial / Q000473:pathology*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C414431:BAG3 protein, human; C498806:Bag3 protein, mouse; D002352:Carrier Proteins; D018840:HSP70 Heat-Shock Proteins; C107953:RAC1 protein, human; D020830:rac1 GTP-Binding Protein