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Off-target effects of protein tyrosine phosphatase inhibitors on oncostatin M-treated human epidermal keratinocytes: the phosphatase targeting STAT1 remains unknown

Cytokine signaling in the epidermis has an important role in maintaining barrier function and is perturbed in pathological conditions. Environmental exposures, such as to metal compounds, are of interest for their potential contribution to skin disease. Present work explores the possibility that van...

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Autores principales: Hong, Brian V., Lee, Ji H., Rice, Robert H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: PeerJ Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430265/
https://www.ncbi.nlm.nih.gov/pubmed/32864202
http://dx.doi.org/10.7717/peerj.9504
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author Hong, Brian V.
Lee, Ji H.
Rice, Robert H.
author_facet Hong, Brian V.
Lee, Ji H.
Rice, Robert H.
author_sort Hong, Brian V.
collection PubMed
description Cytokine signaling in the epidermis has an important role in maintaining barrier function and is perturbed in pathological conditions. Environmental exposures, such as to metal compounds, are of interest for their potential contribution to skin disease. Present work explores the possibility that vanadate is a more effective protein tyrosine phosphatase inhibitor in human keratinocytes than previously observed in fibroblasts. It focuses on the state of phosphorylation of signal transducer and activator of transcription 1 (STAT1) on tyrosine 701 upon treatment of cultured human keratinocytes with the cytokine oncostatin M, a cutaneous inflammatory mediator that is highly effective in suppressing several differentiation markers and in preserving proliferative potential of keratinocytes. Exposure to sodium vanadate in the medium greatly prolonged the phosphorylation of STAT1, but only at high concentration (>30 µM). Inhibitors of protein tyrosine phosphatases known to dephosphorylate STAT1 (SHP2, TCPTP, PTP1B) were ineffective in mimicking the action of vanadate. The irreversible protein tyrosine phosphatase inhibitor phenyl vinyl sulfonate alone induced STAT1 phosphorylation and appeared to induce its limited cleavage. It also inhibited cross-linked envelope formation, a characteristic step of keratinocyte terminal differentiation, likely due to its reaction with the active site cysteine of keratinocyte transglutaminase. Thus, the key protein tyrosine phosphatase responsible for STAT1 dephosphorylation remains to be identified, and an off-target effect of a potential inhibitor was revealed.
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spelling pubmed-74302652020-08-27 Off-target effects of protein tyrosine phosphatase inhibitors on oncostatin M-treated human epidermal keratinocytes: the phosphatase targeting STAT1 remains unknown Hong, Brian V. Lee, Ji H. Rice, Robert H. PeerJ Cell Biology Cytokine signaling in the epidermis has an important role in maintaining barrier function and is perturbed in pathological conditions. Environmental exposures, such as to metal compounds, are of interest for their potential contribution to skin disease. Present work explores the possibility that vanadate is a more effective protein tyrosine phosphatase inhibitor in human keratinocytes than previously observed in fibroblasts. It focuses on the state of phosphorylation of signal transducer and activator of transcription 1 (STAT1) on tyrosine 701 upon treatment of cultured human keratinocytes with the cytokine oncostatin M, a cutaneous inflammatory mediator that is highly effective in suppressing several differentiation markers and in preserving proliferative potential of keratinocytes. Exposure to sodium vanadate in the medium greatly prolonged the phosphorylation of STAT1, but only at high concentration (>30 µM). Inhibitors of protein tyrosine phosphatases known to dephosphorylate STAT1 (SHP2, TCPTP, PTP1B) were ineffective in mimicking the action of vanadate. The irreversible protein tyrosine phosphatase inhibitor phenyl vinyl sulfonate alone induced STAT1 phosphorylation and appeared to induce its limited cleavage. It also inhibited cross-linked envelope formation, a characteristic step of keratinocyte terminal differentiation, likely due to its reaction with the active site cysteine of keratinocyte transglutaminase. Thus, the key protein tyrosine phosphatase responsible for STAT1 dephosphorylation remains to be identified, and an off-target effect of a potential inhibitor was revealed. PeerJ Inc. 2020-08-14 /pmc/articles/PMC7430265/ /pubmed/32864202 http://dx.doi.org/10.7717/peerj.9504 Text en ©2020 Hong et al. https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ) and either DOI or URL of the article must be cited.
spellingShingle Cell Biology
Hong, Brian V.
Lee, Ji H.
Rice, Robert H.
Off-target effects of protein tyrosine phosphatase inhibitors on oncostatin M-treated human epidermal keratinocytes: the phosphatase targeting STAT1 remains unknown
title Off-target effects of protein tyrosine phosphatase inhibitors on oncostatin M-treated human epidermal keratinocytes: the phosphatase targeting STAT1 remains unknown
title_full Off-target effects of protein tyrosine phosphatase inhibitors on oncostatin M-treated human epidermal keratinocytes: the phosphatase targeting STAT1 remains unknown
title_fullStr Off-target effects of protein tyrosine phosphatase inhibitors on oncostatin M-treated human epidermal keratinocytes: the phosphatase targeting STAT1 remains unknown
title_full_unstemmed Off-target effects of protein tyrosine phosphatase inhibitors on oncostatin M-treated human epidermal keratinocytes: the phosphatase targeting STAT1 remains unknown
title_short Off-target effects of protein tyrosine phosphatase inhibitors on oncostatin M-treated human epidermal keratinocytes: the phosphatase targeting STAT1 remains unknown
title_sort off-target effects of protein tyrosine phosphatase inhibitors on oncostatin m-treated human epidermal keratinocytes: the phosphatase targeting stat1 remains unknown
topic Cell Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430265/
https://www.ncbi.nlm.nih.gov/pubmed/32864202
http://dx.doi.org/10.7717/peerj.9504
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