Substrate-biased activity-based probes identify proteases that cleave receptor CDCP1.
Journal
Nature chemical biology
ISSN: 1552-4469
Titre abrégé: Nat Chem Biol
Pays: United States
ID NLM: 101231976
Informations de publication
Date de publication:
07 2021
07 2021
Historique:
received:
14
10
2020
accepted:
04
03
2021
pubmed:
17
4
2021
medline:
8
9
2021
entrez:
16
4
2021
Statut:
ppublish
Résumé
CUB domain-containing protein 1 (CDCP1) is an oncogenic orphan transmembrane receptor and a promising target for the detection and treatment of cancer. Extracellular proteolysis of CDCP1 by poorly defined mechanisms induces pro-metastatic signaling. We describe a new approach for the rapid identification of proteases responsible for key proteolytic events using a substrate-biased activity-based probe (sbABP) that incorporates a substrate cleavage motif grafted onto a peptidyl diphenyl phosphonate warhead for specific target protease capture, isolation and identification. Using a CDCP1-biased probe, we identify urokinase (uPA) as the master regulator of CDCP1 proteolysis, which acts both by directly cleaving CDCP1 and by activating CDCP1-cleaving plasmin. We show that coexpression of uPA and CDCP1 is strongly predictive of poor disease outcome across multiple cancers and demonstrate that uPA-mediated CDCP1 proteolysis promotes metastasis in disease-relevant preclinical in vivo models. These results highlight CDCP1 cleavage as a potential target to disrupt cancer and establish sbABP technology as a new approach to identify disease-relevant proteases.
Identifiants
pubmed: 33859413
doi: 10.1038/s41589-021-00783-w
pii: 10.1038/s41589-021-00783-w
doi:
Substances chimiques
Antigens, Neoplasm
0
CDCP1 protein, human
0
Cell Adhesion Molecules
0
Peptide Hydrolases
EC 3.4.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
776-783Références
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