title: Characterization and mechanism of stress-induced translocation of 78-kilodalton glucose-regulated protein (GRP78) to the cell surface.
abstract: Glucose-regulated protein (GRP78)/BiP, a major chaperone in the endoplasmic reticulum, is recently discovered to be preferably expressed on the surface of stressed cancer cells, where it regulates critical oncogenic signaling pathways and is emerging as a target for anti-cancer therapy while sparing normal organs. However, because GRP78 does not contain classical transmembrane domains, its mechanism of transport and its anchoring at the cell surface are poorly understood. Using a combination of biochemical, mutational, FACS, and single molecule super-resolution imaging approaches, we discovered that GRP78 majorly exists as a peripheral protein on plasma membrane via interaction with other cell surface proteins including glycosylphosphatidylinositol-anchored proteins. Moreover, cell surface GRP78 expression requires its substrate binding activity but is independent of ATP binding or a membrane insertion motif conserved with HSP70. Unexpectedly, different cancer cell lines rely on different mechanisms for GRP78 cell surface translocation, implying that the process is cell context-dependent.
authors: From the Department of Biochemistry and Molecular Biology, University of Southern California, Keck School of Medicine, USC Norris Comprehensive Cancer Center, Los Angeles, California 90089-9176 and.
authors: Yuan-Li
authors: YL
authors: Tsai
authors: From the Department of Biochemistry and Molecular Biology, University of Southern California, Keck School of Medicine, USC Norris Comprehensive Cancer Center, Los Angeles, California 90089-9176 and.
authors: Yi
authors: Y
authors: Zhang
authors: From the Department of Biochemistry and Molecular Biology, University of Southern California, Keck School of Medicine, USC Norris Comprehensive Cancer Center, Los Angeles, California 90089-9176 and.
authors: Chun-Chih
authors: CC
authors: Tseng
authors: Department of Biological Sciences.
authors: Ramunas
authors: R
authors: Stanciauskas
authors: Department of Biological Sciences, Department of Chemistry, and Department of Physics and Astronomy, Dana and David Dornsife College of Letters, Arts, and Sciences, University of Southern California, Los Angeles, California 90089.
authors: Fabien
authors: F
authors: Pinaud
authors: From the Department of Biochemistry and Molecular Biology, University of Southern California, Keck School of Medicine, USC Norris Comprehensive Cancer Center, Los Angeles, California 90089-9176 and amylee@usc.edu.
authors: Amy S
authors: AS
authors: Lee
mesh_terms: D051242:Caveolin 1 / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D058851:GPI-Linked Proteins / Q000378:metabolism; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D011485:Protein Binding; D021382:Protein Sorting Signals; D021381:Protein Transport
chemical_list: D051242:Caveolin 1; D000091342:Endoplasmic Reticulum Chaperone BiP; D058851:GPI-Linked Proteins; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D021382:Protein Sorting Signals
keywords: Cancer Cell Lines; Cell Surface Protein; Chaperone; Endoplasmic Reticulum Stress (ER Stress); GPI-anchored Proteins; GRP78/BiP; Imaging; Translocation