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Reductive stress selectively disrupts collagen homeostasis and modifies growth factor-independent signalling through the MAPK/Akt pathway in human dermal fibroblasts

Carne, NA; Brown, AP; Bell, S; Maatta, A; Flagler, MJ; Benham, AM

Reductive stress selectively disrupts collagen homeostasis and modifies growth factor-independent signalling through the MAPK/Akt pathway in human dermal fibroblasts Thumbnail


Authors

NA Carne

AP Brown

A Maatta

MJ Flagler



Abstract

Redox stress is a well-known contributor to ageing and diseases in skin. Reductants such as dithiothreitol (DTT) can trigger a stress response by disrupting disulfide bonds. However, the quantitative response of the cellular proteome to reductants has not been explored, particularly in cells such as fibroblasts that produce extracellular matrix proteins. Here, we have used a robust, unbiased, label-free SWATH-MS proteomic approach to quantitate the response of skin fibroblast cells to DTT in the presence or absence of the growth factor PDGF. Of the 4487 proteins identified, only 42 proteins showed a statistically significant change of 2-fold or more with reductive stress. Our proteomics data show that reductive stress results in the loss of a small subset of reductant-sensitive proteins (including the collagens COL1A1/2 and COL3A1, and the myopathy-associated collagens COL6A1/2/3), and the downregulation of targets downstream of the MAPK pathway. We show that a reducing environment alters signalling through the PDGF-associated MAPK/Akt pathways, inducing chronic dephosphorylation of ERK1/2 at Thr202/Tyr204 and phosphorylation of Akt at Ser473 in a growth factor-independent manner. Our data highlights collagens as sentinel molecules for redox stress downstream of MAPK/Akt, and identifies intervention points to modulate the redox environment to target skin diseases and conditions associated with erroneous matrix deposition.

Citation

Carne, N., Brown, A., Bell, S., Maatta, A., Flagler, M., & Benham, A. (2019). Reductive stress selectively disrupts collagen homeostasis and modifies growth factor-independent signalling through the MAPK/Akt pathway in human dermal fibroblasts. Molecular and Cellular Proteomics, 18(6), 1123-1137. https://doi.org/10.1074/mcp.ra118.001140

Journal Article Type Article
Acceptance Date Mar 19, 2019
Online Publication Date Mar 19, 2019
Publication Date Jun 1, 2019
Deposit Date Mar 19, 2019
Publicly Available Date Mar 20, 2019
Journal Molecular and Cellular Proteomics
Print ISSN 1535-9476
Electronic ISSN 1535-9484
Publisher American Society for Biochemistry and Molecular Biology
Peer Reviewed Peer Reviewed
Volume 18
Issue 6
Pages 1123-1137
DOI https://doi.org/10.1074/mcp.ra118.001140
Public URL https://durham-repository.worktribe.com/output/1305897

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Copyright Statement
This research was originally published in Carne, NA, Bell, S, Brown, AP , Maatta, A, Flagler MJ & Benham AM (2019). Reductive stress selectively disrupts collagen homeostasis and modifies growth factor-independent signalling through the MAPK/Akt pathway in human dermal fibroblasts. Molecular and Cellular Proteomics 18(6): 1123-1137 © the American Society for Biochemistry and Molecular Biology.







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