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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| Format: | Article |
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PeerJ Inc.
2020-08-01
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| Series: | PeerJ |
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| Online Access: | https://peerj.com/articles/9504.pdf |
| _version_ | 1797418812129148928 |
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| author | Brian V. Hong Ji H. Lee Robert H. Rice |
| author_facet | Brian V. Hong Ji H. Lee Robert H. Rice |
| author_sort | Brian V. Hong |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-09T06:39:23Z |
| format | Article |
| id | doaj.art-85c43afbd8cb440c99871b3db6eb3faf |
| institution | Directory Open Access Journal |
| issn | 2167-8359 |
| language | English |
| last_indexed | 2024-03-09T06:39:23Z |
| publishDate | 2020-08-01 |
| publisher | PeerJ Inc. |
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| spelling | doaj.art-85c43afbd8cb440c99871b3db6eb3faf2023-12-03T10:54:05ZengPeerJ Inc.PeerJ2167-83592020-08-018e950410.7717/peerj.9504Off-target effects of protein tyrosine phosphatase inhibitors on oncostatin M-treated human epidermal keratinocytes: the phosphatase targeting STAT1 remains unknownBrian V. Hong0Ji H. Lee1Robert H. Rice2Department of Environmental Toxicology and Forensic Science Program, University of California, Davis, CA, United States of AmericaDepartment of Environmental Toxicology and Forensic Science Program, University of California, Davis, CA, United States of AmericaDepartment of Environmental Toxicology and Forensic Science Program, University of California, Davis, CA, United States of AmericaCytokine 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.https://peerj.com/articles/9504.pdfCytokinesPVSNSTAT1TransglutaminaseVanadate |
| spellingShingle | Brian V. Hong Ji H. Lee Robert H. Rice Off-target effects of protein tyrosine phosphatase inhibitors on oncostatin M-treated human epidermal keratinocytes: the phosphatase targeting STAT1 remains unknown PeerJ Cytokines PVSN STAT1 Transglutaminase Vanadate |
| 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 | Cytokines PVSN STAT1 Transglutaminase Vanadate |
| url | https://peerj.com/articles/9504.pdf |
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