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https://hdl.handle.net/2440/73924
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dc.contributor.author | Ray, R. | - |
dc.contributor.author | de Ridder, G. | - |
dc.contributor.author | Eu, J. | - |
dc.contributor.author | Paton, A. | - |
dc.contributor.author | Paton, J. | - |
dc.contributor.author | Pizzo, S. | - |
dc.date.issued | 2012 | - |
dc.identifier.citation | Journal of Biological Chemistry, 2012; 287(39):32755-32769 | - |
dc.identifier.issn | 0021-9258 | - |
dc.identifier.issn | 1083-351X | - |
dc.identifier.uri | http://hdl.handle.net/2440/73924 | - |
dc.description.abstract | GRP78, a molecular chaperone with critical endoplasmic reticulum functions, is aberrantly expressed on the surface of cancer cells, including prostate and melanoma. Here it functions as a pro-proliferative and anti-apoptotic signaling receptor via NH2-terminal domain ligation. Auto-antibodies to this domain may appear in cancer patient serum where they are a poor prognostic indicator. Conversely, GRP78 COOH-terminal domain ligation is pro-apoptotic and anti-proliferative. There is no method to disrupt cell-surface GRP78 without compromising the total GRP78 pool, making it difficult to study cell-surface GRP78 function. We studied six cell lines representing three cancer types. One cell line per group expresses high levels of cell-surface GRP78, and the other expresses low levels (human hepatoma: Hep3B and HepG2; human prostate cancer: PC3 and 1-LN; murine melanoma: B16F0 and B16F1). We investigated the effect of Escherichia coli subtilase cytoxin catalytic subunit (SubA) on GRP78. We report that SubA specifically cleaves cell-surface GRP78 on HepG2, 1-LN, and B16F1 cells without affecting intracellular GRP78. B16F0 cells (GRP78low) have lower amounts of cleaved cell-surface GRP78. SubA has no effect on Hep3B and PC3 cells. The predicted 28-kDa GRP78 COOH-terminal fragment is released into the culture medium by SubA treatment, and COOH-terminal domain signal transduction is abrogated, whereas pro-proliferative signaling mediated through NH2-terminal domain ligation is unaffected. These experiments clarify cell-surface GRP78 topology and demonstrate that the COOH-terminal domain is necessary for pro-apoptotic signal transduction occurring upon COOH-terminal antibody ligation. SubA is a powerful tool to specifically probe the functions of cell-surface GRP78. | - |
dc.description.statementofresponsibility | Rupa Ray, Gustaaf G. de Ridder, Jerry P. Eu, Adrienne W. Paton, James C. Paton and Salvatore V. Pizzo | - |
dc.language.iso | en | - |
dc.publisher | Amer Soc Biochemistry Molecular Biology Inc | - |
dc.rights | © 2012 by The American Society for Biochemistry and Molecular Biology, Inc. | - |
dc.source.uri | http://dx.doi.org/10.1074/jbc.m112.399808 | - |
dc.subject | Animals | - |
dc.subject | Humans | - |
dc.subject | Mice | - |
dc.subject | Escherichia coli | - |
dc.subject | Melanoma | - |
dc.subject | Prostatic Neoplasms | - |
dc.subject | Subtilisins | - |
dc.subject | Escherichia coli Proteins | - |
dc.subject | Heat-Shock Proteins | - |
dc.subject | Receptors, G-Protein-Coupled | - |
dc.subject | Antibodies, Neoplasm | - |
dc.subject | Autoantibodies | - |
dc.subject | Signal Transduction | - |
dc.subject | Catalytic Domain | - |
dc.subject | Male | - |
dc.subject | Hep G2 Cells | - |
dc.subject | Proteolysis | - |
dc.title | The Escherichia coli subtilase cytotoxin A subunit specifically cleaves cell-surface GRP78 protein and abolishes COOH-terminal-dependent signaling | - |
dc.type | Journal article | - |
dc.identifier.doi | 10.1074/jbc.M112.399808 | - |
pubs.publication-status | Published | - |
dc.identifier.orcid | Paton, J. [0000-0001-9807-5278] | - |
Appears in Collections: | Aurora harvest 4 Microbiology and Immunology publications |
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