Dataset Information

TAILS proteomics of murine pancreatic tumors

ABSTRACT: Aberrant proteolysis by cysteine cathepsins is implicated in carcinogenesis, but knowledge of cathepsin substrates mediating tumor-promoting or suppressing effects is limited. Here we characterize tumor proteome and in vivo cathepsin substrates using cathepsin knockout mice and the RIP1-Tag2 model of pancreatic islet carcinogenesis. Applying an unbiased systems-level proteomics approach, Terminal Amine Isotopic Labeling of Substrates (TAILS), we identified cysteine cathepsin B, H, L, S, Z substrates and their cleavage sites. Among 1,935 proteins and 1,114 N-termini identified by TAILS using 8-plex iTRAQ protein labeling, 145 neo-N-termini were significantly changed in one (55%) or more knockouts suggesting a lack of direct compensation at substrate level by other cathepsins. Most affected N-termini (56-83% for different cathepsins) represented degradative cathepsin activity, whereas 17-44% of neo-N termini represented stable proteolytic products in the tumors and were enriched for extracellular proteins. We identified candidate substrates for mediating signaling roles of cysteine cathepsins in tumorigenesis.

INSTRUMENT(S): QSTAR

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Pancreas

SUBMITTER: Ulrich auf dem Keller

LAB HEAD: Christopher M. Overall

PROVIDER: PXD003637 | Pride | 2016-08-08

REPOSITORIES: Pride

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

Prudova Anna A Gocheva Vasilena V Auf dem Keller Ulrich U Eckhard Ulrich U Olson Oakley C OC Akkari Leila L Butler Georgina S GS Fortelny Nikolaus N Lange Philipp F PF Mark Jennifer C JC Joyce Johanna A JA Overall Christopher M CM

Cell reports 20160728 6

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, ...[more]

PMID: 27477282

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