Document Detail

Processing of proaugurin is required to suppress proliferation of tumor cell lines.
MedLine Citation:
PMID:  21436262     Owner:  NLM     Status:  MEDLINE    
Augurin is a secretory molecule produced in pituitary, thyroid, and esophagus and implicated in a wide array of physiological processes, from ACTH release to tumor suppression. However, the specific proaugurin-derived peptides present in various cell types are not yet known. In order to shed light on the posttranslational modifications required for biological activity, we here describe the posttranslational processing of proaugurin in AtT-20 and Lovo cells and identify proaugurin-derived products generated by convertases. In vitro cleavage of proaugurin with proprotein convertases produced multiple peptides, including a major product with a mass of 9.7 kDa by mass spectrometry. Metabolic labeling of C-terminally tagged proaugurin in AtT-20 and AtT-20/PC2 cells resulted in a major 15-kDa tagged form on SDS-PAGE, which likely corresponds to the 9.7-kDa in vitro fragment, with the added tag, its linker, and posttranslational modification(s). The secretion of neither proaugurin nor this cleavage product was stimulated by forskolin, indicating its lack of storage in regulated secretory granules and lack of cleavage by PC2. Incubation of cells with the furin inhibitor nona-d-arginine resulted in impaired cleavage of proaugurin, whereas metalloprotease inhibitors did not affect proaugurin proteolysis. These data support the idea that proaugurin is cleaved by furin and secreted via the constitutive secretory pathway. Interestingly, proaugurin was sulfated during trafficking; sulfation was completely inhibited by brefeldin A. Proliferation assays with three different tumor cell lines demonstrated that only furin-cleaved proaugurin could suppress cell proliferation, suggesting that proteolytic cleavage is a posttranslational requirement for proaugurin to suppress cell proliferation.
Akihiko Ozawa; Adam N Lick; Iris Lindberg
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-03-24
Journal Detail:
Title:  Molecular endocrinology (Baltimore, Md.)     Volume:  25     ISSN:  1944-9917     ISO Abbreviation:  Mol. Endocrinol.     Publication Date:  2011 May 
Date Detail:
Created Date:  2011-04-28     Completed Date:  2011-09-26     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  8801431     Medline TA:  Mol Endocrinol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  776-84     Citation Subset:  IM    
Department of Anatomy and Neurobiology, University of Maryland-Baltimore, 20 Penn Street, Baltimore, Maryland 21201, USA.
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MeSH Terms
Amino Acid Sequence
Cell Line, Tumor
Cell Proliferation*
Furin / metabolism
Molecular Sequence Data
Molecular Weight
Neoplasm Proteins / metabolism,  secretion*
Proprotein Convertases / metabolism
Protein Precursors / metabolism,  secretion*
Protein Processing, Post-Translational
Secretory Pathway
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Grant Support
Reg. No./Substance:
0/Neoplasm Proteins; 0/Protein Precursors; 0/esophageal cancer related gene 4 protein, mouse; EC 3.4.-/Proprotein Convertases; EC protein, human; EC

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

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