TAILS N-Terminomics and Proteomics Show Protein Degradation Dominates over Proteolytic Processing by Cathepsins in Pancreatic Tumors.

Détails

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Etat: Serval
Version: Final published version
ID Serval
serval:BIB_EFC4B030CCF3
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
TAILS N-Terminomics and Proteomics Show Protein Degradation Dominates over Proteolytic Processing by Cathepsins in Pancreatic Tumors.
Périodique
Cell reports
Auteur(s)
Prudova A., Gocheva V., Auf dem Keller U., Eckhard U., Olson O.C., Akkari L., Butler G.S., Fortelny N., Lange P.F., Mark J.C., Joyce J.A., Overall C.M.
ISSN
2211-1247 (Electronic)
Statut éditorial
Publié
Date de publication
09/08/2016
Peer-reviewed
Oui
Volume
16
Numéro
6
Pages
1762-1773
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Résumé
Deregulated cathepsin proteolysis occurs across numerous cancers, but in vivo substrates mediating tumorigenesis remain ill-defined. Applying 8-plex iTRAQ terminal amine isotopic labeling of substrates (TAILS), a systems-level N-terminome degradomics approach, we identified cathepsin B, H, L, S, and Z in vivo substrates and cleavage sites with the use of six different cathepsin knockout genotypes in the Rip1-Tag2 mouse model of pancreatic neuroendocrine tumorigenesis. Among 1,935 proteins and 1,114 N termini identified by TAILS, stable proteolytic products were identified in wild-type tumors compared with one or more different cathepsin knockouts (17%-44% of 139 cleavages). This suggests a lack of compensation at the substrate level by other cathepsins. The majority of neo-N termini (56%-83%) for all cathepsins was consistent with protein degradation. We validated substrates, including the glycolytic enzyme pyruvate kinase M2 associated with the Warburg effect, the ER chaperone GRP78, and the oncoprotein prothymosin-alpha. Thus, the identification of cathepsin substrates in tumorigenesis improves the understanding of cathepsin functions in normal physiology and cancer.

Mots-clé
Animals, Carcinogenesis/metabolism, Cathepsins/metabolism, Heat-Shock Proteins/metabolism, Mice, Transgenic, Oncogene Proteins/metabolism, Pancreatic Neoplasms/metabolism, Protein Processing, Post-Translational, Proteome/metabolism, Proteomics/methods, Substrate Specificity/physiology, ECM, TAILS degradomics, cysteine cathepsins, degradation, lysosomal hydrolases, pancreatic neuroendocrine cancer, proteases, proteolytic processing, proteomics, substrate discovery
Pubmed
Web of science
Création de la notice
04/08/2016 18:48
Dernière modification de la notice
03/03/2018 22:35
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