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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 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.

Type Journal
ISBN 1552-4469 (Electronic) 1552-4450 (Linking)
Authors Kryza, T.; Khan, T.; Lovell, S.; Harrington, B. S.; Yin, J.; Porazinski, S.; Pajic, M.; Koistinen, H.; Rantala, J. K.; Dreyer, T.; Magdolen, V.; Reuning, U.; He, Y.; Tate, E. W.; Hooper, J. D.
Responsible Garvan Author A/Prof Marina Pajic
Publisher Name Nature Chemical Biology
Published Date 2021-07-31
Published Volume 17
Published Issue 7
Published Pages 776-783
Status Published in-print
DOI 10.1038/s41589-021-00783-w
URL link to publisher's version