Tyrosine phosphorylation allows integration of multiple signaling inputs by IKKβ.
Signaling regulated by NFκB and related transcription factors is centrally important to many inflammatory and autoimmune diseases, cancer, and stress responses. The kinase that directly regulates the canonical NFκB transcriptional pathway, Inhibitor of κB kinase β (IKKβ), undergoes activation by Ser...
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Public Library of Science (PLoS)
2013
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oai:doaj.org-article:94e790c838bc4b7db7445582e2055c142021-11-18T08:40:04ZTyrosine phosphorylation allows integration of multiple signaling inputs by IKKβ.1932-620310.1371/journal.pone.0084497https://doaj.org/article/94e790c838bc4b7db7445582e2055c142013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24386391/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Signaling regulated by NFκB and related transcription factors is centrally important to many inflammatory and autoimmune diseases, cancer, and stress responses. The kinase that directly regulates the canonical NFκB transcriptional pathway, Inhibitor of κB kinase β (IKKβ), undergoes activation by Ser phosphorylation mediated by NIK or TAK1 in response to inflammatory signals. Using titanium dioxide-based phosphopeptide enrichment (TiO2)-liquid chromatography (LC)-high mass accuracy tandem mass spectrometry (MS/MS), we analyzed IKKβ phosphorylation in human HEK293 cells expressing IKKβ and FGFR2, a Receptor tyrosine kinase (RTK) essential for embryonic differentiation and dysregulated in several cancers. We attained unusually high coverage of IKKβ, identifying an abundant site of Tyr phosphorylation at Tyr169 within the Activation Loop. The phosphomimic at this site confers a level of kinase activation and NFκB nuclear localization exceeding the iconic mutant S177E/S181E, demonstrating that RTK-mediated Tyr phosphorylation of IKKβ has the potential to directly regulate NFκB transcriptional activation.April N MeyerKristine A DrafahlChristopher W McAndrewJennifer E GildaLeandro H GalloMartin HaasLaurence M BrillDaniel J DonoghuePublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 12, p e84497 (2013) |
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Medicine R Science Q |
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Medicine R Science Q April N Meyer Kristine A Drafahl Christopher W McAndrew Jennifer E Gilda Leandro H Gallo Martin Haas Laurence M Brill Daniel J Donoghue Tyrosine phosphorylation allows integration of multiple signaling inputs by IKKβ. |
| description |
Signaling regulated by NFκB and related transcription factors is centrally important to many inflammatory and autoimmune diseases, cancer, and stress responses. The kinase that directly regulates the canonical NFκB transcriptional pathway, Inhibitor of κB kinase β (IKKβ), undergoes activation by Ser phosphorylation mediated by NIK or TAK1 in response to inflammatory signals. Using titanium dioxide-based phosphopeptide enrichment (TiO2)-liquid chromatography (LC)-high mass accuracy tandem mass spectrometry (MS/MS), we analyzed IKKβ phosphorylation in human HEK293 cells expressing IKKβ and FGFR2, a Receptor tyrosine kinase (RTK) essential for embryonic differentiation and dysregulated in several cancers. We attained unusually high coverage of IKKβ, identifying an abundant site of Tyr phosphorylation at Tyr169 within the Activation Loop. The phosphomimic at this site confers a level of kinase activation and NFκB nuclear localization exceeding the iconic mutant S177E/S181E, demonstrating that RTK-mediated Tyr phosphorylation of IKKβ has the potential to directly regulate NFκB transcriptional activation. |
| format |
article |
| author |
April N Meyer Kristine A Drafahl Christopher W McAndrew Jennifer E Gilda Leandro H Gallo Martin Haas Laurence M Brill Daniel J Donoghue |
| author_facet |
April N Meyer Kristine A Drafahl Christopher W McAndrew Jennifer E Gilda Leandro H Gallo Martin Haas Laurence M Brill Daniel J Donoghue |
| author_sort |
April N Meyer |
| title |
Tyrosine phosphorylation allows integration of multiple signaling inputs by IKKβ. |
| title_short |
Tyrosine phosphorylation allows integration of multiple signaling inputs by IKKβ. |
| title_full |
Tyrosine phosphorylation allows integration of multiple signaling inputs by IKKβ. |
| title_fullStr |
Tyrosine phosphorylation allows integration of multiple signaling inputs by IKKβ. |
| title_full_unstemmed |
Tyrosine phosphorylation allows integration of multiple signaling inputs by IKKβ. |
| title_sort |
tyrosine phosphorylation allows integration of multiple signaling inputs by ikkβ. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2013 |
| url |
https://doaj.org/article/94e790c838bc4b7db7445582e2055c14 |
| work_keys_str_mv |
AT aprilnmeyer tyrosinephosphorylationallowsintegrationofmultiplesignalinginputsbyikkb AT kristineadrafahl tyrosinephosphorylationallowsintegrationofmultiplesignalinginputsbyikkb AT christopherwmcandrew tyrosinephosphorylationallowsintegrationofmultiplesignalinginputsbyikkb AT jenniferegilda tyrosinephosphorylationallowsintegrationofmultiplesignalinginputsbyikkb AT leandrohgallo tyrosinephosphorylationallowsintegrationofmultiplesignalinginputsbyikkb AT martinhaas tyrosinephosphorylationallowsintegrationofmultiplesignalinginputsbyikkb AT laurencembrill tyrosinephosphorylationallowsintegrationofmultiplesignalinginputsbyikkb AT danieljdonoghue tyrosinephosphorylationallowsintegrationofmultiplesignalinginputsbyikkb |
| _version_ |
1718421514898898944 |