Biochem. J. (2014) 463, e1–e2 (Printed in Great Britain)
e1
doi:10.1042/BJ20140989
COMMENTARY
Priming IKKβ kinase for action Steven C. LEY* and Rudi BEYAERT†‡1 *Division of Immune Cell Biology, Medical Research Council National Institute for Medical Research, London, U.K. †Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium ‡Inflammation Research Center, Unit of Molecular Signal Transduction in Inflammation, VIB, Ghent, Belgium
IKKβ (IκB kinase β) is a core component of signalling pathways that control the activation of NF-κB (nuclear factor κB) transcription factors, which regulate many physiological processes, including cell survival, immunity and DNA-damage responses. Like many kinases, activation of IKKβ requires phosphorylation of the activation loop of its kinase domain. Different upstream protein kinases, and IKKβ itself, have been reported to directly phosphorylate and activate IKKβ in vitro, but the exact molecular mechanism of IKKβ activation in cells has remained unclear. In a recent article in the Biochemical Journal, Zhang and co-workers showed that IKKβ is activated by two sequential phosphorylations of its activation loop in response to TNF (tumour necrosis factor), IL-1 (interleukin-
1) and TLR (Toll-like receptor) ligands. Using a combination of biochemical and genetic approaches, they demonstrate that IKKβ is first phosphorylated by the upstream kinase TAK1 [TGFβ (transforming growth factor β)-activated kinase-1] at Ser177 , which then serves as a priming signal for subsequent IKKβ autophosphorylation at Ser181 . This study resolves two apparently conflicting earlier models of IKKβ activation into a single unified model, and suggests that the IKKβ activation loop may integrate distinct ‘upsteam’ signals to activate NF-κB.
The NF-κB (nuclear factor κB) transcription factor family controls the expression of hundreds of genes that are involved in many physiological processes, including inflammation, immunity, cell proliferation and cell death [1]. Dysregulated NF-κB activation is involved in many autoimmune diseases and certain cancers. NF-κB is normally kept inactive in the cytoplasm via binding to IκB (inhibitor of NF-κB) family proteins. Canonical NF-κB stimuli, such as pro-inflammatory cytokines and microbial products, trigger the phosphorylation of IκBα, promoting its Lys48 -linked polyubiquitination and degradation by the proteasome to release associated p50–RelA and p50–cRel. As a consequence, NF-κB dimers can move freely into the nucleus where they bind the regulatory elements of a variety of genes and promote transcription. The main kinase responsible for the phosphorylation of IκBα is IKK (IκB kinase) β, which is part of a large complex that includes the related protein kinase IKKα and NEMO (NF-κB essential modulator), an essential ubiquitinbinding regulatory subunit [2]. IKKα mainly functions in the alternative NF-κB pathway that regulates the activation of NFκB2 p52–RelB dimers in response to a subset of TNF (tumour necrosis factor) family members. Activation of IKKβ requires phosphorylation of two serine residues (Ser177 and Ser181 ) in its activation loop, which probably induces a conformational change [2]. The MAPK (mitogen-activated protein kinase) TAK1 (transforming growth factor β-activated kinase-1) can function as an IKK kinase, which is required for activation of NF-κB by certain agonists [3]. However, some experimental evidence indicates that IKKβ autophosphorylation, triggered by stimulus-dependent conformational changes or oligomerization, is required for NF-κB
activation [4]. It has remained unclear whether IKKβ is activated by an upstream kinase or by stimulus-induced oligomerization. In a recent paper in the Biochemical Journal, Cohen and co-workers show that both regulatory processes appear to be involved in IKKβ activation [5]. Previous studies investigating the role of phosphorylation in IKKβ activation made use of a phospho-specific antibody that recognizes the diphosphorylated species modified at both Ser177 and Ser181 , which did not allow the detection of differences in IKKβ phosphorylation of the two regulatory serine residues. To circumvent this problem, Zhang et al. [5] monitored the dual phosphorylation of IKKβ using phospho-specific antibodies that recognize IKKβ phosphorylated at either Ser177 or Ser181 . These studies led to the unexpected observation that pharmacological inhibition of IKKβ suppressed the TNF- or IL-1 (interleukin-1)-stimulated phosphorylation of Ser181 , but not of Ser177 . In contrast, pharmacological inhibition of TAK1 prevented the phosphorylation at both Ser177 and Ser181 . To exclude a possible role for IKKα, which can also phosphorylate IKKβ at Ser181 , these studies were performed with IKKα-deficient MEF (mouse embryonic fibroblast) cells. Similar results were obtained with LPS (lipopolysaccharide)and Pam3 CSK4 (tripalmitoylated Cys-Ser-Lys4 )-stimulated bonemarrow-derived macrophages from knock-in mice expressing a catalytically inactive IKKα mutant, demonstrating their general significance. Together these results are compatible with a model in which TAK1 phosphorylates Ser177 , priming IKKβ-catalysed autophosphorylation on Ser181 . To obtain further proof for this priming model, the authors generated IKKα-deficient MEF cells that stably expressed an IKKβ[S177E] mutant, mimicking the effect of phosphorylation
Key words: inflammation, inhibitor of NF-κB kinase β (IKKβ), nuclear factor κB (NF-κB), transforming growth factor β-activated kinase-1 (TAK1), phosphorylation, ubiquitination.
Abbreviations: IκB, inhibitor of NF-κB; IKK, IκB kinase; IL-1, interleukin-1; IRAK1, IL-1 receptor-associated kinase 1; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; MEF, mouse embryonic fibroblast; NEMO, NF-κB essential modulator; NF-κB, nuclear factor κB; Pam3 CSK4 , tripalmitoylated Cys-Ser-Lys4 ; TAB, TAK1-binding protein; TAK1, TGFβ (transforming growth factor β)-activated kinase-1; TNF, tumour necrosis factor; TLR, Toll-like receptor. 1 To whom correspondence should be addressed (email [email protected]). c The Authors Journal compilation c 2014 Biochemical Society
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at Ser177 by introducing a negative charge. This mutant became phosphorylated at Ser181 without any cell stimulus, which underwent dephosphorylation when cells were incubated with an IKKβ inhibitor, but not a TAK1 inhibitor. Furthermore, expression of a catalytically inactive mutant version of IKKβ[S177E] failed to undergo Ser181 phosphorylation. These data demonstrate that the phosphomimetic S177E mutation permits IKKβ to autophosphorylate at Ser181 , further supporting a model in which agonist stimulation induces TAK1 to phosphorylate IKKβ Ser177 , priming IKKβ autophosphorylation at Ser181 . The aforementioned experiments were obtained with IKKαdeficient MEFs or macrophages expressing a catalytically inactive IKKα mutant. In wild-type cells, IKKα and IKKβ form a single IKK complex together with NEMO, raising the possibility that IKKβ could also be activated in trans by IKKα, as suggested by earlier transient transfection experiments [6]. In line with this possibility, IKKβ inhibition of TNF- or IL-1stimulated wild-type MEF cells only slightly decreased IKKβ Ser181 phosphorylation, suggesting that phosphorylation of primed IKKβ on Ser181 is catalysed by IKKα transphosphorylation when IKKβ autophosphorylation is blocked. Extensive research over the past 10 years has revealed important roles for Lys63 -linked and Met1 -linked polyubiquitination of several NF-κB signalling proteins, which serve to recruit proteins or protein complexes to polyubiquitinated substrates [7]. Binding of the TAK1 adaptor proteins TAB (TAK1-binding protein) -2 and -3 to Lys63 -linked polyubiquitin chains can recruit the TAK1 complex to Lys63 polyubiquitinated substrates, whereas binding of the IKK adaptor protein NEMO to Met1 -linked polyubiquitin chains can recruit the IKK complex to Met1 polyubiquitinated substrates. Recent work has shown that these two interactions may not occur on separate ubiquitin chains. IL-1β stimulation was shown to induce IRAK1 (IL-1 receptor-associated kinase 1) modification by Lys63 /Met1 -linked hybrid polyubiquitin chains, which may promote the simultaneous recruitment of TAK1 and IKK complexes facilitating TAK1-mediated activation of IKKβ [8]. Zhang et al. [5] also investigated whether the sequential phosphorylation of Ser177 and Ser181 in IKKβ requires the formation of Met1 -linked polyubiquitin chains and their specific binding to NEMO. IL-1-stimulated phosphorylation of IKKβ Ser177 and Ser181 was shown to be impaired in MEF cells derived from specific knock-in mice expressing a catalytic inactive HOIP mutant (which is the only E3 ubiquitin ligase that is known to form Met1 -linked polyubiquitin chains) or a Met1 polyubiquitin-binding-deficient NEMO mutant, compared with wild-type MEFs. Thus the formation of Met1 -linked polyubiquitin chains and their interaction with the NEMO component of the IKK complex are essential for TAK1-mediated priming of IKKβ. These data are consistent with a model in which the IL-1-induced modification of specific signalling proteins with Lys63 /Met1 -linked hybrid polyubiquitin chains allows the colocalization of TAK1 and IKK complexes, facilitating the TAK1mediated phosphorylation and activation of IKKβ. A possible alternative explanation for the reduced dual phosphorylation of IKKβ in HOIP and NEMO mutant cells could be that activation of TAK1 is impaired in such cells. However, this possibility was excluded by the demonstration that the TAK1-mediated activation of JNK1/JNK2 and p38α MAPKs was not affected in these cells. Received 1 August 2014; accepted 5 August 2014 Published on the Internet 8 September 2014, doi:10.1042/BJ20140989
c The Authors Journal compilation c 2014 Biochemical Society
Zhang et al. [5] clearly demonstrate the role of TAK1 priming for IKKβ activation by TNFR1 (TNF receptor 1), IL-1R (IL-1 receptor), TLR1/2 (Toll-like receptor 1/2) and TLR4. However, this mechanism may not be universal and operate in a cellular context-dependent way. For example, studies of cells derived from cell-type-specific TAK1-deficient mice revealed that TAK1 is dispensable for NF-κB signalling in TCR (T-cell receptor)stimulated effector T-cells [9] and even negatively regulates LPS-induced IKK activation in mouse neutrophils [10]. It will therefore be of interest to identify the upstream kinases that are responsible for IKK phosphorylation and activation in these cell types. Another question to solve is how TAK1 obtains specificity for Ser177 since Zhang et al. [5] show that in vitro TAK1 is capable of phosphorylating IKKβ at both Ser177 and Ser181 . Possibly, in cells the positioning of TAK1 and IKKβ at polyubiquitinated substrates creates a platform that directs TAK1 catalytic activity specifically to Ser177 . Protein kinases often require the phosphorylation of two amino acid residues in their activation loop, which in most cases is thought to be catalysed by a single protein kinase. The work of Zhang et al. [5] raises the possibility that such kinases may in fact be regulated by two separate activation loop kinases. Given that cells must simultaneously integrate multiple signals to regulate a complex set of cellular processes and that there is considerable cross-talk between individual signalling pathways, the need for two different kinases to activate another kinase may be a widespread mechanism to deal with this complexity. The identification of more such examples can be expected to provide valuable information towards the design of more effective therapeutics.
REFERENCES 1 Vallabhapurapu, S. and Karin, M. (2009) Regulation and function of NF-κB transcription factors in the immune system. Annu. Rev. Immunol. 27, 693–733 CrossRef PubMed 2 H¨acker, H. and Karin, M. (2006) Regulation and function of IKK and IKK-related kinases. Sci. STKE 2006 357, re13 PubMed 3 Ajibade, A. A., Wang, H. Y. and Wang, R. F. (2013) Cell type-specific function of TAK1 in innate immune signaling. Trends Immunol. 34, 307–316 CrossRef PubMed 4 Tang, E. D., Inohara, N., Wang, C. Y., Nu˜nez, G. and Guan, K. L. (2003) Roles for homotypic interactions and transautophosphorylation in IκB kinase β activation. J. Biol. Chem. 278, 38566–38570 CrossRef PubMed 5 Zhang, J., Clark, K., Lawrence, T., Peggie, M. W. and Cohen, P. (2014) An unexpected twist to the activation of IKKβ: TAK1 primes IKKβ for activation by autophosphorylation. Biochem. J. 461, 531–537 CrossRef PubMed 6 O’Mahony, A., Lin, X., Geleziunas, R. and Greene, W. C. (2000) Activation of the heterodimeric IκB kinase α (IKKα)-IKKβ complex is directional: IKKα regulates IKKβ under both basal and stimulated conditions. Mol. Cell. Biol. 20, 1170–1178 CrossRef PubMed 7 Clark, K., Nanda, S. and Cohen, P. (2013) Molecular control of the NEMO family of ubiquitin-binding proteins. Nat. Rev. Mol. Cell Biol. 14, 673–685 CrossRef PubMed 8 Emmerich, C. H., Ordureau, A., Strickson, S., Arthur, J. S., Pedrioli, P. G., Komander, D. and Cohen, P. (2013) Activation of the canonical IKK complex by K63/M1-linked hybrid ubiquitin chains. Proc. Natl. Acad. Sci. U.S.A. 110, 15247–15252 CrossRef PubMed 9 Wan, Y. Y., Chi, H., Xie, M., Schneider, M. D. and Flavell, R. A. (2006) The kinase TAK1 integrates antigen and cytokine receptor signaling for T cell development, survival and function. Nat. Immunol. 7, 851–858 CrossRef PubMed 10 Ajibade, A. A., Wang, Q., Cui, J., Zou, J., Xia, X., Wang, M., Tong, Y., Hui, W., Liu, D., Su, B. et al. (2012) TAK1 negatively regulates NF-κB and p38 MAP kinase activation in Gr-1 + CD11b + neutrophils. Immunity 36, 43–54 CrossRef PubMed
Copyright of Biochemical Journal is the property of Portland Press Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
e1
doi:10.1042/BJ20140989
COMMENTARY
Priming IKKβ kinase for action Steven C. LEY* and Rudi BEYAERT†‡1 *Division of Immune Cell Biology, Medical Research Council National Institute for Medical Research, London, U.K. †Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium ‡Inflammation Research Center, Unit of Molecular Signal Transduction in Inflammation, VIB, Ghent, Belgium
IKKβ (IκB kinase β) is a core component of signalling pathways that control the activation of NF-κB (nuclear factor κB) transcription factors, which regulate many physiological processes, including cell survival, immunity and DNA-damage responses. Like many kinases, activation of IKKβ requires phosphorylation of the activation loop of its kinase domain. Different upstream protein kinases, and IKKβ itself, have been reported to directly phosphorylate and activate IKKβ in vitro, but the exact molecular mechanism of IKKβ activation in cells has remained unclear. In a recent article in the Biochemical Journal, Zhang and co-workers showed that IKKβ is activated by two sequential phosphorylations of its activation loop in response to TNF (tumour necrosis factor), IL-1 (interleukin-
1) and TLR (Toll-like receptor) ligands. Using a combination of biochemical and genetic approaches, they demonstrate that IKKβ is first phosphorylated by the upstream kinase TAK1 [TGFβ (transforming growth factor β)-activated kinase-1] at Ser177 , which then serves as a priming signal for subsequent IKKβ autophosphorylation at Ser181 . This study resolves two apparently conflicting earlier models of IKKβ activation into a single unified model, and suggests that the IKKβ activation loop may integrate distinct ‘upsteam’ signals to activate NF-κB.
The NF-κB (nuclear factor κB) transcription factor family controls the expression of hundreds of genes that are involved in many physiological processes, including inflammation, immunity, cell proliferation and cell death [1]. Dysregulated NF-κB activation is involved in many autoimmune diseases and certain cancers. NF-κB is normally kept inactive in the cytoplasm via binding to IκB (inhibitor of NF-κB) family proteins. Canonical NF-κB stimuli, such as pro-inflammatory cytokines and microbial products, trigger the phosphorylation of IκBα, promoting its Lys48 -linked polyubiquitination and degradation by the proteasome to release associated p50–RelA and p50–cRel. As a consequence, NF-κB dimers can move freely into the nucleus where they bind the regulatory elements of a variety of genes and promote transcription. The main kinase responsible for the phosphorylation of IκBα is IKK (IκB kinase) β, which is part of a large complex that includes the related protein kinase IKKα and NEMO (NF-κB essential modulator), an essential ubiquitinbinding regulatory subunit [2]. IKKα mainly functions in the alternative NF-κB pathway that regulates the activation of NFκB2 p52–RelB dimers in response to a subset of TNF (tumour necrosis factor) family members. Activation of IKKβ requires phosphorylation of two serine residues (Ser177 and Ser181 ) in its activation loop, which probably induces a conformational change [2]. The MAPK (mitogen-activated protein kinase) TAK1 (transforming growth factor β-activated kinase-1) can function as an IKK kinase, which is required for activation of NF-κB by certain agonists [3]. However, some experimental evidence indicates that IKKβ autophosphorylation, triggered by stimulus-dependent conformational changes or oligomerization, is required for NF-κB
activation [4]. It has remained unclear whether IKKβ is activated by an upstream kinase or by stimulus-induced oligomerization. In a recent paper in the Biochemical Journal, Cohen and co-workers show that both regulatory processes appear to be involved in IKKβ activation [5]. Previous studies investigating the role of phosphorylation in IKKβ activation made use of a phospho-specific antibody that recognizes the diphosphorylated species modified at both Ser177 and Ser181 , which did not allow the detection of differences in IKKβ phosphorylation of the two regulatory serine residues. To circumvent this problem, Zhang et al. [5] monitored the dual phosphorylation of IKKβ using phospho-specific antibodies that recognize IKKβ phosphorylated at either Ser177 or Ser181 . These studies led to the unexpected observation that pharmacological inhibition of IKKβ suppressed the TNF- or IL-1 (interleukin-1)-stimulated phosphorylation of Ser181 , but not of Ser177 . In contrast, pharmacological inhibition of TAK1 prevented the phosphorylation at both Ser177 and Ser181 . To exclude a possible role for IKKα, which can also phosphorylate IKKβ at Ser181 , these studies were performed with IKKα-deficient MEF (mouse embryonic fibroblast) cells. Similar results were obtained with LPS (lipopolysaccharide)and Pam3 CSK4 (tripalmitoylated Cys-Ser-Lys4 )-stimulated bonemarrow-derived macrophages from knock-in mice expressing a catalytically inactive IKKα mutant, demonstrating their general significance. Together these results are compatible with a model in which TAK1 phosphorylates Ser177 , priming IKKβ-catalysed autophosphorylation on Ser181 . To obtain further proof for this priming model, the authors generated IKKα-deficient MEF cells that stably expressed an IKKβ[S177E] mutant, mimicking the effect of phosphorylation
Key words: inflammation, inhibitor of NF-κB kinase β (IKKβ), nuclear factor κB (NF-κB), transforming growth factor β-activated kinase-1 (TAK1), phosphorylation, ubiquitination.
Abbreviations: IκB, inhibitor of NF-κB; IKK, IκB kinase; IL-1, interleukin-1; IRAK1, IL-1 receptor-associated kinase 1; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; MEF, mouse embryonic fibroblast; NEMO, NF-κB essential modulator; NF-κB, nuclear factor κB; Pam3 CSK4 , tripalmitoylated Cys-Ser-Lys4 ; TAB, TAK1-binding protein; TAK1, TGFβ (transforming growth factor β)-activated kinase-1; TNF, tumour necrosis factor; TLR, Toll-like receptor. 1 To whom correspondence should be addressed (email [email protected]). c The Authors Journal compilation c 2014 Biochemical Society
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at Ser177 by introducing a negative charge. This mutant became phosphorylated at Ser181 without any cell stimulus, which underwent dephosphorylation when cells were incubated with an IKKβ inhibitor, but not a TAK1 inhibitor. Furthermore, expression of a catalytically inactive mutant version of IKKβ[S177E] failed to undergo Ser181 phosphorylation. These data demonstrate that the phosphomimetic S177E mutation permits IKKβ to autophosphorylate at Ser181 , further supporting a model in which agonist stimulation induces TAK1 to phosphorylate IKKβ Ser177 , priming IKKβ autophosphorylation at Ser181 . The aforementioned experiments were obtained with IKKαdeficient MEFs or macrophages expressing a catalytically inactive IKKα mutant. In wild-type cells, IKKα and IKKβ form a single IKK complex together with NEMO, raising the possibility that IKKβ could also be activated in trans by IKKα, as suggested by earlier transient transfection experiments [6]. In line with this possibility, IKKβ inhibition of TNF- or IL-1stimulated wild-type MEF cells only slightly decreased IKKβ Ser181 phosphorylation, suggesting that phosphorylation of primed IKKβ on Ser181 is catalysed by IKKα transphosphorylation when IKKβ autophosphorylation is blocked. Extensive research over the past 10 years has revealed important roles for Lys63 -linked and Met1 -linked polyubiquitination of several NF-κB signalling proteins, which serve to recruit proteins or protein complexes to polyubiquitinated substrates [7]. Binding of the TAK1 adaptor proteins TAB (TAK1-binding protein) -2 and -3 to Lys63 -linked polyubiquitin chains can recruit the TAK1 complex to Lys63 polyubiquitinated substrates, whereas binding of the IKK adaptor protein NEMO to Met1 -linked polyubiquitin chains can recruit the IKK complex to Met1 polyubiquitinated substrates. Recent work has shown that these two interactions may not occur on separate ubiquitin chains. IL-1β stimulation was shown to induce IRAK1 (IL-1 receptor-associated kinase 1) modification by Lys63 /Met1 -linked hybrid polyubiquitin chains, which may promote the simultaneous recruitment of TAK1 and IKK complexes facilitating TAK1-mediated activation of IKKβ [8]. Zhang et al. [5] also investigated whether the sequential phosphorylation of Ser177 and Ser181 in IKKβ requires the formation of Met1 -linked polyubiquitin chains and their specific binding to NEMO. IL-1-stimulated phosphorylation of IKKβ Ser177 and Ser181 was shown to be impaired in MEF cells derived from specific knock-in mice expressing a catalytic inactive HOIP mutant (which is the only E3 ubiquitin ligase that is known to form Met1 -linked polyubiquitin chains) or a Met1 polyubiquitin-binding-deficient NEMO mutant, compared with wild-type MEFs. Thus the formation of Met1 -linked polyubiquitin chains and their interaction with the NEMO component of the IKK complex are essential for TAK1-mediated priming of IKKβ. These data are consistent with a model in which the IL-1-induced modification of specific signalling proteins with Lys63 /Met1 -linked hybrid polyubiquitin chains allows the colocalization of TAK1 and IKK complexes, facilitating the TAK1mediated phosphorylation and activation of IKKβ. A possible alternative explanation for the reduced dual phosphorylation of IKKβ in HOIP and NEMO mutant cells could be that activation of TAK1 is impaired in such cells. However, this possibility was excluded by the demonstration that the TAK1-mediated activation of JNK1/JNK2 and p38α MAPKs was not affected in these cells. Received 1 August 2014; accepted 5 August 2014 Published on the Internet 8 September 2014, doi:10.1042/BJ20140989
c The Authors Journal compilation c 2014 Biochemical Society
Zhang et al. [5] clearly demonstrate the role of TAK1 priming for IKKβ activation by TNFR1 (TNF receptor 1), IL-1R (IL-1 receptor), TLR1/2 (Toll-like receptor 1/2) and TLR4. However, this mechanism may not be universal and operate in a cellular context-dependent way. For example, studies of cells derived from cell-type-specific TAK1-deficient mice revealed that TAK1 is dispensable for NF-κB signalling in TCR (T-cell receptor)stimulated effector T-cells [9] and even negatively regulates LPS-induced IKK activation in mouse neutrophils [10]. It will therefore be of interest to identify the upstream kinases that are responsible for IKK phosphorylation and activation in these cell types. Another question to solve is how TAK1 obtains specificity for Ser177 since Zhang et al. [5] show that in vitro TAK1 is capable of phosphorylating IKKβ at both Ser177 and Ser181 . Possibly, in cells the positioning of TAK1 and IKKβ at polyubiquitinated substrates creates a platform that directs TAK1 catalytic activity specifically to Ser177 . Protein kinases often require the phosphorylation of two amino acid residues in their activation loop, which in most cases is thought to be catalysed by a single protein kinase. The work of Zhang et al. [5] raises the possibility that such kinases may in fact be regulated by two separate activation loop kinases. Given that cells must simultaneously integrate multiple signals to regulate a complex set of cellular processes and that there is considerable cross-talk between individual signalling pathways, the need for two different kinases to activate another kinase may be a widespread mechanism to deal with this complexity. The identification of more such examples can be expected to provide valuable information towards the design of more effective therapeutics.
REFERENCES 1 Vallabhapurapu, S. and Karin, M. (2009) Regulation and function of NF-κB transcription factors in the immune system. Annu. Rev. Immunol. 27, 693–733 CrossRef PubMed 2 H¨acker, H. and Karin, M. (2006) Regulation and function of IKK and IKK-related kinases. Sci. STKE 2006 357, re13 PubMed 3 Ajibade, A. A., Wang, H. Y. and Wang, R. F. (2013) Cell type-specific function of TAK1 in innate immune signaling. Trends Immunol. 34, 307–316 CrossRef PubMed 4 Tang, E. D., Inohara, N., Wang, C. Y., Nu˜nez, G. and Guan, K. L. (2003) Roles for homotypic interactions and transautophosphorylation in IκB kinase β activation. J. Biol. Chem. 278, 38566–38570 CrossRef PubMed 5 Zhang, J., Clark, K., Lawrence, T., Peggie, M. W. and Cohen, P. (2014) An unexpected twist to the activation of IKKβ: TAK1 primes IKKβ for activation by autophosphorylation. Biochem. J. 461, 531–537 CrossRef PubMed 6 O’Mahony, A., Lin, X., Geleziunas, R. and Greene, W. C. (2000) Activation of the heterodimeric IκB kinase α (IKKα)-IKKβ complex is directional: IKKα regulates IKKβ under both basal and stimulated conditions. Mol. Cell. Biol. 20, 1170–1178 CrossRef PubMed 7 Clark, K., Nanda, S. and Cohen, P. (2013) Molecular control of the NEMO family of ubiquitin-binding proteins. Nat. Rev. Mol. Cell Biol. 14, 673–685 CrossRef PubMed 8 Emmerich, C. H., Ordureau, A., Strickson, S., Arthur, J. S., Pedrioli, P. G., Komander, D. and Cohen, P. (2013) Activation of the canonical IKK complex by K63/M1-linked hybrid ubiquitin chains. Proc. Natl. Acad. Sci. U.S.A. 110, 15247–15252 CrossRef PubMed 9 Wan, Y. Y., Chi, H., Xie, M., Schneider, M. D. and Flavell, R. A. (2006) The kinase TAK1 integrates antigen and cytokine receptor signaling for T cell development, survival and function. Nat. Immunol. 7, 851–858 CrossRef PubMed 10 Ajibade, A. A., Wang, Q., Cui, J., Zou, J., Xia, X., Wang, M., Tong, Y., Hui, W., Liu, D., Su, B. et al. (2012) TAK1 negatively regulates NF-κB and p38 MAP kinase activation in Gr-1 + CD11b + neutrophils. Immunity 36, 43–54 CrossRef PubMed
Copyright of Biochemical Journal is the property of Portland Press Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
