An Historical Perspective: Cell Surface GRP78, a New Paradigm in Signal Transduction Biology
This chapter will present a historical perspective with respect to the presence of Glucose Regulated Protein 78,000 (GRP78) on the cell surface. Its presence there was completely unexpected since this protein normally functions as a molecular chaperone within the endoplasmic reticulum. When it appears on the cell surface, most particularly of cancer cells, it functions as a cell surface receptor coupled to signaling cascades which are pro-proliferative, antiapoptotic, and promigratory. Studies have identified antibodies in the plasma of cancer patients which bind to the amino-terminal domain of GRP78 where natural ligands also bind, functioning as agonistics. These antibodies are markers suggesting a poor prognosis. By contrast, antibodies which bind to the carboxyl-terminal domain block cancer cell proliferation and migration while promoting apoptosis. Thus, cell surface-associated GRP78 offers a new target for cancer therapy, particularly employing monoclonal antibodies.