The anti-inflammatory compound BAY 11-7082 is a potent inhibitor of Protein Tyrosine Phosphatases

Krishnan, N., Bencze, G., Cohen, P., Tonks, N. K. (2013) The anti-inflammatory compound BAY 11-7082 is a potent inhibitor of Protein Tyrosine Phosphatases. FEBS Journal, 280 (12). pp. 2830-2841. ISSN 1742-464X

URL: http://www.ncbi.nlm.nih.gov/pubmed/23578302
DOI: 10.1111/febs.12283

Abstract

The families of protein tyrosine phosphatases (PTPs) and protein tyrosine kinases (PTKs) function in a coordinated manner to regulate signal transduction events that are critical for cellular homeostasis. Aberrant tyrosine phosphorylation, resulting from disruption of either PTP or PTK function, has been shown to be the cause of major human diseases, including cancer and diabetes. Consequently, the characterization of small molecule inhibitors of these kinases and phosphatases may not only provide molecular probes with which to define the significance of particular signalling events, but also may have therapeutic implications. BAY 11-7082 is an anti-inflammatory compound that has been reported to inhibit IkappaB kinase activity. The compound has an alpha,beta-unsaturated electrophilic center, which confers the property of being a Michael acceptor; this suggests that it may react with nucleophilic cysteine-containing proteins, such as PTPs. In this study, we demonstrated that BAY 11-7082 was a potent, irreversible inhibitor of PTPs. Using mass spectrometry, we have shown that BAY 11-7082 inactivated PTPs by forming a covalent adduct with the active site cysteine. Administration of the compound caused an increase in protein tyrosine phosphorylation in RAW 264 macrophages, similar to the effects of the generic PTP inhibitor sodium orthovanadate. These data illustrate that BAY 11-7082 is an effective pan-PTP inhibitor with cell permeability, revealing its potential as a new probe for chemical biology approaches to the study of PTP function. Furthermore, the data suggest that inhibition of PTP function may contribute to the many biological effects of BAY 11-7082 that have been reported to date. This article is protected by copyright. All rights reserved.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > protein tyrosine phosphatase
CSHL Authors:
Communities: CSHL Cancer Center Program > Signal Transduction
CSHL Cancer Center Shared Resources > DNA Sequencing Service
CSHL Cancer Center Shared Resources > Proteomics Service
CSHL Post Doctoral Fellows
CSHL labs > Tonks lab
CSHL Cancer Center Shared Resources > Mass Spectrometry Service
Depositing User: Matt Covey
Date Deposited: 23 May 2013 14:58
Last Modified: 30 Oct 2015 14:30
PMCID: PMC3712534
Related URLs:
URI: http://repository.cshl.edu/id/eprint/28323

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