Substrate-biased activity-based probes identify proteases that cleave receptor CDCP1

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 identific...

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Vydáno v:	Nature chemical biology Ročník 17; číslo 7; s. 776 - 783
Hlavní autoři:	Kryza, Thomas, Khan, Tashbib, Lovell, Scott, Harrington, Brittney S., Yin, Julia, Porazinski, Sean, Pajic, Marina, Koistinen, Hannu, Rantala, Juha K., Dreyer, Tobias, Magdolen, Viktor, Reuning, Ute, He, Yaowu, Tate, Edward W., Hooper, John D.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	New York Nature Publishing Group US 01.07.2021 Nature Publishing Group
Témata:	631/67 631/92/468 631/92/613 631/92/96 Animals Antigens, Neoplasm - chemistry Antigens, Neoplasm - genetics Antigens, Neoplasm - metabolism Biochemical Engineering Biochemistry Biology Bioorganic Chemistry Cancer Cell Adhesion Molecules - chemistry Cell Adhesion Molecules - genetics Cell Adhesion Molecules - metabolism Cell Biology Chemistry Chemistry and Materials Science Chemistry/Food Science Cleavage Enzymes Humans Metastases Metastasis Mice Mice, Inbred NOD Mice, SCID Molecular Structure Peptide Hydrolases - analysis Peptide Hydrolases - metabolism Peptides Phosphonates Physiology Plasmin Prostate cancer Proteins Proteolysis Receptors Substrate Specificity Substrates Target detection Thrombolytic drugs U-Plasminogen activator Urokinase
ISSN:	1552-4450, 1552-4469, 1552-4469
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Shrnutí:	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. A substrate-biased activity-based probe technology was developed to enable relatively facile identification of proteases responsible for specific proteolytic events in complex biological milieu, revealing that urokinase regulates CDCP1 proteolysis.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1552-4450 1552-4469 1552-4469
DOI:	10.1038/s41589-021-00783-w