Chapter 3 - Cell Surface GRP78: Anchoring and Translocation Mechanisms and Therapeutic Potential in Cancer

Abstract

The Glucose-Regulated Protein 78kDa (GRP78) is an essential chaperone traditionally known to reside in the endoplasmic reticulum (ER) and plays a major role in regulating the unfolded protein response in cells subjected to ER stress. Studies have revealed that ER stress actively promotes the relocalization of GRP78 and other ER chaperones bearing the KDEL motif to the cell surface, where they assume distinct functions impacting proliferation, survival, and death. Toward understanding how GRP78 exerts its functions on the cell surface, it was discovered that the trafficking routes for GRP78 to the cell surface can be Golgi-dependent or -independent in different cell types. A repertoire of protein ligands, transmembrane, and GPI-anchored proteins that interact with cell surface GRP78 have been identified and this provides new information on how their partnerships with cell surface GRP78 contribute to oncogenic signaling, cell adhesion, and modulation of apoptosis. With the preferential expression of GRP78 on the surface of cancer cells, but not normal cells in vivo, opens up the possibility of utilizing cell surface GRP78 as a target for therapy as well as for cancer-specific delivery of therapeutic agents, with minimal damage to normal cells. Knowledge gained from GRP78 may also apply to other ER chaperones performing new cellular functions beyond the ER.