Document Detail


The Escherichia coli subtilase cytotoxin A subunit specifically cleaves cell-surface GRP78 protein and abolishes COOH-terminal-dependent signaling.
MedLine Citation:
PMID:  22851173     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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 NH(2)-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 (GRP78(low)) 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 NH(2)-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.
Authors:
Rupa Ray; Gustaaf G de Ridder; Jerry P Eu; Adrienne W Paton; James C Paton; Salvatore V Pizzo
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Publication Detail:
Type:  Journal Article     Date:  2012-07-31
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  287     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-09-24     Completed Date:  2012-12-07     Revised Date:  2013-09-24    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  32755-69     Citation Subset:  IM    
Affiliation:
Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antibodies, Neoplasm / genetics,  metabolism
Autoantibodies / genetics,  metabolism
Catalytic Domain
Escherichia coli / enzymology*
Escherichia coli Proteins / pharmacology*
Heat-Shock Proteins / genetics,  metabolism*
Hep G2 Cells
Humans
Male
Melanoma / genetics,  metabolism*
Mice
Prostatic Neoplasms / genetics,  metabolism*
Proteolysis / drug effects*
Receptors, G-Protein-Coupled / genetics,  metabolism*
Signal Transduction / drug effects*
Subtilisins / pharmacology*
Chemical
Reg. No./Substance:
0/Antibodies, Neoplasm; 0/Autoantibodies; 0/Escherichia coli Proteins; 0/G protein-coupled receptor GPR78, human; 0/Heat-Shock Proteins; 0/Receptors, G-Protein-Coupled; 0/molecular chaperone GRP78; EC 3.4.21.-/Subtilisins; EC 3.4.21.-/subtilase cytotoxin, E coli
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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