Cell surface translocation mechanism of stress-inducible GRP78 in human cancer

2019-07-12GRP78 is an essential chaperone traditionally known to reside in the endoplasmic reticulum (ER) and plays a major role in regulating the unfolded protein response in cells subjected to ER stress. Recent studies have revealed that ER stress actively promotes the re-localization of GRP78 and other ER chaperones bearing the KDEL motifs to the cell surface, where they assume distinct functions impacting proliferation, survival and death. However, little is known about the underlying mechanisms and the interacting partners on the cell surface. In this dissertation, it is discovered that cell surface GRP78 is a peripheral protein that interacts with repertoire of protein ligands, transmembrane and GPI-anchored proteins. ❧ Towards understanding how GRP78 exerts its functions on the cell surface, it was discovered that the trafficking routes for GRP78 to the cell surface can be Golgi-dependent or -independent in different cell types. Both proto-oncogene tyrosine-protein kinase SRC and TGF-β are important players in cell signaling, growth, apoptosis, and survival. Our discoveries that SRC activation is the driving force in the escape of ER lumenal proteins to the cell surface via disruption of retrograde transport provide a novel oncogenic function for SRC and uncover a mechanism for regulation of TGF-β signaling via the cell surface GRP78/CD109 partnership. It is further revealed that GRP78 depends on endosomal transport to bypass Golgi and express on the cell surface which is general in colon cancer cells. For the therapeutic aspects, with the preferential expression of GRP78 on the surface of cancer cells but not normal cells in vivo opens up the possibility of utilizing cell surface GRP78 as a target for therapy as well as for cancer-specific delivery of therapeutic agents, with minimal damage to normal cells. Knowledge gained from GRP78 may also apply to other ER chaperones performing new cellular functions beyond the ER