Our laboratory has historically studied proteinases and their regulation by the plasma proteinase inhibitor α₂-macroglobulin (α₂M).  When α₂M is "activated" (α₂M*) by interacting with a proteinase, it binds to cell surface receptors which rapidly remove the complexes from the external environment.  The first receptor characterized was the low density lipoprotein-related receptor (K_d 1-5 mM, ~100,000-200,000 receptors/cell).  LRP is a scavenger receptor which binds and internalizes a number of ligands. Beginning in the 1990's we identified a second, very high affinity receptor (K_d 50-100 pM, 5,000-10,000 receptors/cell).  Unlike LRP, this α₂M* receptor is coupled to signal transduction cascades (1).  α₂M* binds to the NH₂-terminal domain where it activates pro-proliferative, anti-apoptotic, and pro-promigratory signaling (1-6).  This receptor is most prominently found on the surface of malignant, but not normal cells (4-6).  This includes prostate, breast, lung, colon, stomach, lung, and ovarian cancers among others.  It was identified by our laboratory as cell surface-associated GRP78 (4).  This was a surprising observation since all previous studies indicated that GRP78, the lynchpin of the unfolded protein response, occurs only in the ER.  Here it functions to promote proper folding of proteins, particularly in highly stressed cells. Cancer cells, by definition, are highly stressed and express high levels of intra-ER GRP78.  Apparently in such cells a fraction of this protein "leaks" to the cell surface, functioning as a G protein-coupled receptor (1-6). Studies beginning in 2003 demonstrated that auto-antibodies directed against GRP may occur in the serum of patients harboring various malignancies.  The occurrence of these auto-antibodies is a harbinger of a poor prognosis. We demonstrated that these auto-antibodies bind to or near the α₂M* binding site and they function as agonists acting like α₂M* (7), thus explaining the association with a poor prognosis.  As a cell surface receptor, GRP78 has essentially unique properties.  Both the NH₂- and COOH-terminal domains are exposed on the cell surface (8).  Our studies remarkably found that ligation of the COOH-terminal domain triggers signaling cascades that are anti-proliferative, pro-apoptotic, and anti-migratory (9). Such dual functionality is not known for any other receptor.  Importantly, ligation of the COOH-terminal domain, while it does not block binding to the NH₂-terminal domain, overrides the pro-proliferative effects of ligating the α₂M* binding site (9).  These antibodies, which do not appear in the sera of patients with highly malignant tumors, have significant therapeutic potential.  Interestingly, cell surface GRP78 is associated with stem cell-like tumor cells, which are resistant to chemotherapy and against which there are no specific drugs (10, 11).  We continue to also characterize the α₂M* signaling cascade. Extensive recent work demonstrates that α₂M* is a more potent regulator of glucose and lipid metabolism than insulin in cancer cells, but not normal cells (12).  The models studied in our laboratory include prostate, brain, ovary, and breast cancer.  Our collaborative interactions with the laboratory of Dr. Robin Bachelder have implicated cell surface GRP78 in cancer stem-like behaviors, including multi-drug resistance (10, 11).