Outside the Endoplasmic Reticulum: Non-Canonical GRP78 Signaling

Abstract

Glucose-regulated protein 78 is best known for its protein chaperone activities and as acting as a molecular switch controlling the unfolded protein response signaling pathway within the endoplasmic reticulum. GRP78 binds to the three arms of the unfolded protein response rendering each pathway inactive. In the presence of unfolded or misfolded proteins, GRP78 unbinds from the three signaling arms, thus enabling UPR activation. However, GRP78 is ubiquitously localized within other cellular compartments and has varied molecular signaling functions depending upon its localization. GRP78 is found on the cell membranes to control cellular growth and differentiation pathways, GRP78 is found on mitochondria, GRP78 regulates cellular energetic pathways and metabolism, GRP78 controls apoptosis and cell death pathway signaling, GRP78 modulates autophagy, and GRP78 affects immune cell activities. We will review the pleiotropic activities of GRP78 outside of its normal UPR functions and discuss GRP78 signaling in cancer in this book chapter.