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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Bibliographic Details
Published in:Nature chemical biology Vol. 17; no. 7; pp. 776 - 783
Main Authors: 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.
Format: Journal Article
Language:English
Published: New York Nature Publishing Group US 01.07.2021
Nature Publishing Group
Subjects:
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
Online Access:Get full text
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Summary: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.
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ISSN:1552-4450
1552-4469
1552-4469
DOI:10.1038/s41589-021-00783-w