BAG3: a multifaceted protein that regulates major cell pathways

Rosati, A; Graziano, V; De Laurenzi, V; Pascale, M; Turco, M C

It has been shown that bag3 silencing reduces adhesion and/or motility of epithelial (breast, prostate) tumor cells. 27, 32, 65, 66 In MDA435 human breast cancer cells, BAG3 overexpression resulted in a decrease in migration and adhesion to matrix molecules; the decrease was reversed on deletion of the BAG3 proline-rich (PXXP) domain, indicating that an interaction of BAG3 with a SH 3 domain-containing protein was involved. 65 Expression array studies showed that indeed BAG3 regulated, in a PXXP-dependent manner, the expression of CCN (Cyr61, connective tissue growth, NOV) 1, a matricellular signaling protein that promotes cell adhesion through integrins and heparan sulfate-containing proteoglycans. 32 In addition, BAG3 seems to regulate cell adhesion through binding to guanine nucleotide exchange factor 2 (PDZGEF2). This protein induces the activation of Rap1, a regulator of cell-cell junction formation and remodeling, and increases integrin-mediated cell adhesion. The PPDY motif at the C-terminus of PDZGEF2 was shown to bind to the WW domain of BAG3, and PDZGEF2 knockdown reduced BAG3 ability to induce cell adhesion in Cos7 cells. 67 Similarly to what we described above for apoptosis, the ability of BAG3 to regulate cell adhesion appears to rely on multiple interactions of this protein through different structural domains. It is important to note that modulation of cell adhesion has profound effects on cell vitality, as cell detachment from matrix induces the apoptotic process known as anoikis. 68 Therefore, BAG3 alterations could underlie effects on both cell detachment/motility and resistance to associated anoikis, thereby favouring metastatization. Finally, we recently reported that BAG3, through its interaction with the cytosolic chaperonin CCT (chaperonin containing TCP-1), regulates actin folding. 66 This property of BAG3 highlights its involvement in cytoskeleton organization, possibly influencing not only cell survival and migration, but also membrane trafficking and organellar dynamics.