TAILS N-terminomics and proteomics show protein degradation dominates over proteolytic processing by cathepsins in pancreatic tumors Journal Article
| Authors: | 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. |
| Article Title: | TAILS N-terminomics and proteomics show protein degradation dominates over proteolytic processing by cathepsins in pancreatic tumors |
| Abstract: | 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. © 2016 The Author(s) |
| Keywords: | signal transduction; controlled study; sequence analysis; nonhuman; protein function; mass spectrometry; protein analysis; animal cell; mouse; tumor volume; protein degradation; animal experiment; animal model; proteomics; carcinogenesis; protein processing; regulatory mechanism; amino terminal sequence; cathepsin; cathepsin b; protein cleavage; degradation; tumor microenvironment; cathepsin l; cathepsin s; cathepsin h; proteases; pancreatic neuroendocrine tumor; cysteine cathepsins; glucose regulated protein 78; pyruvate kinase; pancreatic neuroendocrine cancer; priority journal; article; proteolytic processing; ecm; cathepsin x; lysosomal hydrolases; substrate discovery; tails degradomics; prothymosin alpha; terminal amine isotopic labeling of substrates |
| Journal Title: | Cell Reports |
| Volume: | 16 |
| Issue: | 6 |
| ISSN: | 2211-1247 |
| Publisher: | Cell Press |
| Date Published: | 2016-08-09 |
| Start Page: | 1762 |
| End Page: | 1773 |
| Language: | English |
| DOI: | 10.1016/j.celrep.2016.06.086 |
| PROVIDER: | scopus |
| PUBMED: | 27477282 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 November 2016 -- Source: Scopus |
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