Substrate-biased activity-based probes identify proteases that cleave receptor CDCP1
| Autor: | Thomas Kryza, Ute Reuning, Tobias Dreyer, Marina Pajic, Viktor Magdolen, Yaowu He, Julia Yin, Juha Rantala, Edward W. Tate, Hannu Koistinen, Scott Lovell, Brittney S. Harrington, Tashbib Khan, John D. Hooper, Sean Porazinski |
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| Přispěvatelé: | Engineering and Physical Sciences Research Council |
| Rok vydání: | 2020 |
| Předmět: |
Biochemistry & Molecular Biology
Proteases Plasmin Proteolysis medicine.medical_treatment Mice SCID 0601 Biochemistry and Cell Biology Cleavage (embryo) Substrate Specificity 03 medical and health sciences Mice Antigens Neoplasm Mice Inbred NOD medicine Animals Humans Receptor Molecular Biology 030304 developmental biology 0303 health sciences Science & Technology Protease 0304 Medicinal and Biomolecular Chemistry medicine.diagnostic_test Molecular Structure Chemistry 030302 biochemistry & molecular biology Cell Biology Transmembrane protein Cell biology CDCP1 Life Sciences & Biomedicine Cell Adhesion Molecules medicine.drug Peptide Hydrolases |
| Zdroj: | Nature chemical biology. 17(7) |
| ISSN: | 1552-4469 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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