Cellular and Molecular Biology


GRP78: A chaperone with diverse roles beyond the endoplasmic reticulum

Quintin J. Quinones*, Gustaaf G. de Ridder* and Salvatore V. Pizzo

Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA
*These authors contributed equally

Offprint requests to: Dr. Salvatore V. Pizzo, Duke University Medical Center, Department of Pathology, Box 3712, Durham, North Carolina 27710, USA. e-mail: pizzo001@mc.duke.edu

Summary. Glucose-regulated protein 78 (GRP78) is a well-characterized molecular chaperone that is ubiquitously expressed in mammalian cells. GRP78 is best known for binding to hydrophobic patches on nascent polypeptides within the endoplasmic reticulum (ER) and for its role in signaling the unfolded protein response. Structurally, GRP78 is highly conserved across species. The presence of GRP78 or a homologue in nearly every organism from bacteria to man, reflects the central roles it plays in cell survival. While the principal role of GRP78 as a molecular chaperone is a matter of continuing study, independent work demonstrates that like many other proteins with ancient origins, GRP78 plays more roles than originally appreciated. Studies have shown that GRP78 is expressed on the cell surface in many tissue types both in vitro and in vivo. Cell surface GRP78 is involved in transducing signals from ligands as disparate as activated α2-macroglobulin and antibodies. Plasmalemmar GRP78 also plays a role in viral entry of Coxsackie B, and Dengue Fever viruses. GRP78 disregulation is also implicated in atherosclerotic, thrombotic, and auto-immune disease. It is challenging to posit a hypothesis as to why an ER molecular chaperone, such as GRP78, plays such a variety of roles in cellular processes. An ancient and highly conserved protein such as GRP78, whose primary function is to bind to misfolded polypeptides, could be uniquely suited to bind a wide variety of ligands and thus, over time, could assume the wide variety of roles it now plays. Histol Histopathol 23, 1409-1416 (2008)

Key words: GRP78, Plasma Membrane, Signaling, Unfolded Protein Response, Cell Surface

DOI: 10.14670/HH-23.1409