Chapter 4 Cell Surface GRP78 A Novel Regulator of Tissue Factor Procoagulant Activity

The Glucose Regulated Protein 78,000 (GRP78) is an endoplasmic reticulum (ER)-resident chaperone responsible for ensuring that newly synthesized polypeptides entering the ER are properly folded into functional proteins. Under normal physiological conditions, GRP78 associates with IRE-1, ATF-6 and PERK, ER membrane proteins that modulate the unfolded protein response (UPR). Following the accumulation of misfolded/unfolded proteins within the ER, GRP78 dissociates from IRE-1, ATF-6, and/or PERK, thereby aiding in the folding of such unfolded/misfolded proteins and activating the UPR. In terms of its protein structure, GRP78 contains a C-terminal ER-retention motif, KDEL, allowing for its localization to the ER. Surprisingly, GRP78 can escape ER retention and cell surface levels are detected in various pathological conditions such as rheumatoid arthritis, atherosclerosis, and many cancers, including melanoma and prostate cancer. The presentation of GRP78 on the cell surface is associated with a new antigenic property of the protein leading to the production of anti-GRP78 autoantibodies. Studies have shown that the binding of anti-GRP78 autoantibodies to cell surface GRP78 elicit an intracellular response involving increased production of IP3 molecules in the cytoplasm; IP3 molecules can bind to specific ER Ca2+ channels that lead to increased cytoplasmic Ca2+ levels. Further, such an increase in cytoplasmic Ca2+ levels is known to induce a membrane phosphatidylserine symmetry and increase activation of tissue factors, the major regulator of coagulation (in blood) and mediator of angiogenesis (in cancer).