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Cathepsin Protease Controls Copper and Cisplatin Accumulation via Cleavage of the Ctr1 Metal-binding Ectodomain
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Duke Univ, Sch Med, Dept Pharmacol & Canc Biol, Box 3813,Res Dr,LSRC C134, Durham, NC 27710 USA..
Duke Univ, Sch Med, Dept Pharmacol & Canc Biol, Box 3813,Res Dr,LSRC C134, Durham, NC 27710 USA..
Jozef Stefan Inst, Dept Biochem & Mol & Struct Biol, SI-1000 Ljubljana, Slovenia.;Univ Ljubljana, Fac Chem & Chem Technol, SI-1000 Ljubljana, Slovenia..
Univ Freiburg, Inst Mol Med & Cell Res, Fac Med, D-79104 Freiburg, Germany.;Univ Freiburg, BIOSS Ctr Biol Signalling Studies, D-79104 Freiburg, Germany..
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2016 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 291, no 27, 13905-13916 p.Article in journal (Refereed) PublishedText
Abstract [en]

Copper is an essential metal ion for embryonic development, iron acquisition, cardiac function, neuropeptide biogenesis, and other critical physiological processes. Ctr1 is a high affinity Cu+ transporter on the plasma membrane and endosomes that exists as a full-length protein and a truncated form of Ctr1 lacking the methionine- and histidine-rich metal-binding ectodomain, and it exhibits reduced Cu+ transport activity. Here, we identify the cathepsin L/B endolysosomal proteases functioning in a direct and rate-limiting step in the Ctr1 ectodomain cleavage. Cells and mice lacking cathepsin L accumulate full-length Ctr1 and hyper-accumulate copper. As Ctr1 also transports the chemotherapeutic drug cisplatin via direct binding to the ectodomain, we demonstrate that the combination of cisplatin with a cathepsin L/B inhibitor enhances cisplatin uptake and cell killing. These studies identify a new processing event and the key protease that cleaves the Ctr1 metal-binding ectodomain, which functions to regulate cellular Cu+ and cisplatin acquisition.

Place, publisher, year, edition, pages
2016. Vol. 291, no 27, 13905-13916 p.
Keyword [en]
copper transport, cysteine protease, intracellular processing, metal homeostasis, protein processing, anti-cancer drug, cathepsin, cisplatin
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-301426DOI: 10.1074/jbc.M116.731281ISI: 000379975100001PubMedID: 27143361OAI: oai:DiVA.org:uu-301426DiVA: diva2:954589
Funder
NIH (National Institute of Health), DK074192Swedish Research Council, 524-2014-1Åke Wiberg Foundation, M14-0080Magnus Bergvall Foundation, 2014-00058German Research Foundation (DFG), Re1584/6-1 SFB850
Note

De två första författarna delar på första författarskapet.

Available from: 2016-08-23 Created: 2016-08-23 Last updated: 2016-08-23Bibliographically approved

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Öhrvik, Helena
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