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

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Title: Substrate-biased activity-based probes identify proteases that cleave receptor CDCP1
Authors: Kryza, T
Khan, T
Lovell, S
Harrington, BS
Yin, J
Porazinski, S
Pajic, M
Koistinen, H
Rantala, JK
Dreyer, T
Magdolen, V
Reuning, U
He, Y
Tate, EW
Hooper, JD
Item Type: Journal Article
Abstract: 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.
Issue Date: 15-Apr-2021
Date of Acceptance: 4-Mar-2021
URI: http://hdl.handle.net/10044/1/91052
DOI: 10.1038/s41589-021-00783-w
ISSN: 1552-4450
Publisher: Nature Research
Start Page: 776
End Page: 783
Journal / Book Title: Nature Chemical Biology
Volume: 17
Issue: 7
Copyright Statement: © The Author(s), under exclusive licence to Springer Nature America, Inc. 2021. The final publication is available at Springer via https://doi.org/10.1038/s41589-021-00783-w
Sponsor/Funder: Engineering and Physical Sciences Research Council
Funder's Grant Number: EP/R512540/1
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Biochemistry & Molecular Biology
0304 Medicinal and Biomolecular Chemistry
0601 Biochemistry and Cell Biology
Publication Status: Published
Embargo Date: 2022-09-03
Online Publication Date: 2021-04-15
Appears in Collections:Chemistry
Biological and Biophysical Chemistry