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Quantitative Proteomics Reveals Changes Induced by TIMP-3 on Cell Membrane Composition and Novel Metalloprotease Substrates

Authors: Veronica M. Pravata; Elisa Monaca; Matteo Calligaris; Matteo Calligaris; Danilo D'Apolito; Anna Paola Carreca; Simone D. Scilabra; +4 Authors

Quantitative Proteomics Reveals Changes Induced by TIMP-3 on Cell Membrane Composition and Novel Metalloprotease Substrates

Abstract

Ectodomain shedding is a key mechanism of several biological processes, including cell-communication. Disintegrin and metalloproteinases (ADAMs), together with the membrane-type matrix metalloproteinases, play a pivotal role in shedding transmembrane proteins. Aberrant shedding is associated to several pathological conditions, including arthritis. Tissue inhibitor of metalloproteases 3 (TIMP-3), an endogenous inhibitor of ADAMs and matrix metalloproteases (MMPs), has been proven to be beneficial in such diseases. Thus, strategies to increase TIMP-3 bioavailability in the tissue have been sought for development of therapeutics. Nevertheless, high levels of TIMP-3 may lead to mechanism-based side-effects, as its overall effects on cell behavior are still unknown. In this study, we used a high-resolution mass-spectrometry-based workflow to analyze alterations induced by sustained expression of TIMP-3 in the cell surfaceome. In agreement with its multifunctional properties, TIMP-3 induced changes on the protein composition of the cell surface. We found that TIMP-3 had differential effects on metalloproteinase substrates, with several that accumulated in TIMP-3-overexpressing cells. In addition, our study identified potentially novel ADAM substrates, including ADAM15, whose levels at the cell surface are regulated by the inhibitor. In conclusion, our study reveals that high levels of TIMP-3 induce modifications in the cell surfaceome and identifies molecular pathways that can be deregulated via TIMP-3-based therapies.

Countries
United Kingdom, Germany
Keywords

Proteomics, /dk/atira/pure/subjectarea/asjc/1300/1312, Proteome, Ectodomain shedding, 610, ADAM15 protein, human, chemistry [Cell Membrane], metabolism [Cell Membrane], metalloproteinases, Article, Mass Spectrometry, proteomics, Tissue inhibitor of metalloproteases 3 (TIMP-3), Humans, analysis [Proteome], /dk/atira/pure/subjectarea/asjc/1600/1606, Tissue Inhibitor of Metalloproteinase-3, /dk/atira/pure/subjectarea/asjc/1600/1607, /dk/atira/pure/subjectarea/asjc/1700/1706, /dk/atira/pure/subjectarea/asjc/1600/1604, /dk/atira/pure/subjectarea/asjc/1600/1605, name=Inorganic Chemistry, Cell Membrane, Membrane Proteins, tissue inhibitor of metalloproteases 3 (TIMP-3), name=Molecular Biology, name=Computer Science Applications, metabolism [Proteome], 540, Metalloproteinases, name=Spectroscopy, ADAM Proteins, HEK293 Cells, name=Organic Chemistry, metabolism [ADAM Proteins], TIMP3 protein, human, ectodomain shedding, name=Catalysis, metabolism [Tissue Inhibitor of Metalloproteinase-3], metabolism [Membrane Proteins], /dk/atira/pure/subjectarea/asjc/1500/1503, name=Physical and Theoretical Chemistry, ddc: ddc:, ddc: ddc:540

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citations
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
6
Top 10%
Average
Top 10%
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gold