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The anti‐inflammatory compound BAY ‐11‐7082 is a potent inhibitor of protein tyrosine phosphatases
Author(s) -
Krishnan Navasona,
Bencze Gyula,
Cohen Philip,
Tonks Nicholas K.
Publication year - 2013
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.12283
Subject(s) - protein tyrosine phosphatase , chemistry , biochemistry , phosphorylation , kinase , signal transduction , tyrosine , active site , tyrosine kinase , tyrosine phosphorylation , microbiology and biotechnology , biology , enzyme
The families of protein tyrosine phosphatases ( PTP s) and protein tyrosine kinases ( PTK s) 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 signaling events, but also may have therapeutic implications. BAY ‐11‐7082 is an anti‐inflammatory compound that has been reported to inhibit IκB kinase activity. The compound has an α,β‐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 PTP s. In this study, we demonstrated that BAY ‐11‐7082 was a potent, irreversible inhibitor of PTP s. Using mass spectrometry, we have shown that BAY ‐11‐7082 inactivated PTP s 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.