Differential regulation of TROP2 release by PKC isoforms through vesicles and ADAM17

Wanger, Tim M., Dewitt, Sharon ORCID: https://orcid.org/0000-0001-8169-8241, Collins, Anne, Maitland, Norman J., Poghosyan, Zaruhi and Knauper, Vera ORCID: https://orcid.org/0000-0002-3965-9924 2015. Differential regulation of TROP2 release by PKC isoforms through vesicles and ADAM17. Cellular Signalling 27 (7) , pp. 1325-1335. 10.1016/j.cellsig.2015.03.017

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Abstract

TROP2, a cancer cell surface protein with both pro-oncogenic and anti-oncogenic properties is cleaved by ADAM17. ADAM17 dependent cleavage requires novel PKC activity which is blocked by the ADAM10/ADAM17 inhibitor GW64 as well as by the PKC inhibitor Bim-1. Full length TROP2 release is induced by classical PKC activation and blocked by Gö6979, without affecting ADAM17 dependent TROP2 cleavage. Full length TROP2 is released in ectosomes, as inhibition of endocytosis did not prevent release. Inhibition of the atypical PKC isoform PKCζ stimulated metalloproteinase dependent N-terminal alternative TROP2 cleavage. The resulting alternative TROP2 cleavage product remains membrane associated via a disulphide bond, but is released in microvesicles with an average size of 107 nm. Inhibition of endocytosis following PKCζ inhibition prevented alternative cleavage and release of TROP2, suggesting that these events require endocytic uptake and exosomal release of the corresponding microvesicles. The alternative TROP2 cleavage product was also found in PC3 cell lysates following deglycosylation, and may represent a novel biomarker in prostate cancer.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Dentistry
Subjects:	R Medicine > RK Dentistry
Publisher:	Elsevier
ISSN:	0898-6568
Funders:	Tenovus (PhD2011/L25) and Cancer Research Wales
Date of First Compliant Deposit:	30 March 2016
Date of Acceptance:	15 March 2015
Last Modified:	05 Nov 2024 17:30
URI:	https://orca.cardiff.ac.uk/id/eprint/72435

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