The Endoplasmic Reticulum Chaperone GRP78 Also Functions as a Cell Surface Signaling Receptor

The Glucose Regulated Protein 78,000 (GRP78) is a member of the heat shock protein family in the endoplasmic reticulum to regulate protein quality control and degradation. We and others demonstrated that GRP78 is preferentially translocated onto the cell surface (CS-GRP78) and plays a novel role in cellular signaling, proliferation, migration, invasion, apoptosis, inflammation, and immunity which have major implications in cancer progression. CS-GRP78 acts as a multifunctional receptor by interacting with various ligands and other cell surface proteins to control key oncogenic signaling pathways. Activated α2-macroglobulin (α2M*) signals predominately through CS-GRP78 to regulate transcriptional activation of target genes, and, modulates metabolic regulation which might be an adaptive mechanism in rapidly proliferating cancer cells. Therapeutic agents against CS-GRP78 have the potential to target tumor cells with minimal harmful effects on normal cells. This review will focus on our understanding of CS-GRP78 and their influence on fundamental biological processes as well as its targeting agents which hold great therapeutic promise.