Roles of GRP78 in physiology and cancer

Abstract

As one member of 70 kDa heat shock proteins, glucose-regulated protein 78 (GRP78) participates in protein folding, transportation and degradation. This sort of capacity can be enhanced by stresses under which GRP78 is induced rapidly. Unlike its homologues, GRP78 presents multifaceted subcellular position: When ER retention, it serves as the switch of unfolded protein response; When mitochondrial binding, it directly interacts with apoptotic executors; When cell surface residing, it recognizes extracellular ligands, transducing proliferative signals, especially in certain tumors. The close correlation between GRP78 and neoplasm provides us further insight into the event of carcinogenesis and cancer cell chemoresistance, indicating its prognostic predicting significance and validating potential therapeutics for clinical usage, especially because its small molecular inhibitors are emerging quickly these years. What's more, GRP78-related signaling may be helpful for clearer understanding of its biological mechanisms.

Visceral Adipose Tissue-derived Serine Proteinase Inhibitor Inhibits Apoptosis of Endothelial Cells as a Ligand for the Cell-Surface GRP78/Voltage-dependent Anion Channel Complex

“…Thus, blocking anti-GRP78 antibodies, small molecule inhibitors, anticancer agent conjugated with vehicle targeted to GRP78, or GRP78 promoter-driven expression of suicide genes may be expected in the treatment of cancers. 12 Vaspin indeed has a beneficial role in ameliorating vascular dysfunction; future studies are required to address the concern that vaspin or its mimetics may promote the tumor growth by acting on the cell surface GRP78 on tumors cells.…”

“…11 Beyond the ER retention, GRP78 is also associated with various anchor membrane proteins on the cell surface and functions as a receptor for various ligands and a signaling hub for either in cell survival or cell death. [12][13][14][15] Recently, we demonstrated that vaspin ameliorates ER stress and insulin resistance under obese states by acting as a ligand for cell-surface GRP78/MTJ-1 (murine tumor cell DnaJ-like protein-1) complex in the liver. 16 Here, we show vaspin exerts antiapoptotic potential to the endothelial cells and it protects from the vascular injuries in a balloon-injured model in Wistar rats with streptozotocin-induced diabetes mellitus.…”

Edaravone improves spatial memory and modulates endoplasmic reticulum stress-mediated apoptosis after abdominal surgery in mice

“…CHOP is a transcription factor, the physiological level of which is relatively low; however, the protein expression of CHOP may be strongly induced in response to ERS under diverse pathological conditions (28). Similarly, upregulated expression of GRP78 is often regarded as an indicator of ERS (29).…”

Anks4b, a Novel Target of HNF4α Protein, Interacts with GRP78 Protein and Regulates Endoplasmic Reticulum Stress-induced Apoptosis in Pancreatic β-Cells

“…4B). GRP78 is an ER-localized chaperone protein that is induced by the unfolded protein response in response to ER stress (26,27). Binding of GRP78 to GST-FL-Anks4b and GST-M-Anks4b, but not to GST, GST-N-Anks4b, or C-Anks4b, was confirmed by Western blotting using a specific antibody for GRP78 (Fig.…”