NF-κB (nuclear factor-κB) is a collective name for inducible dimeric transcription factors composed of members of the Rel family of DNA-binding proteins that recognize a common sequence motif. NF-κ...

Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity.

Signal transduction by the JNK group of MAP kinases.

The transcription factor NF-kappaB has been the focus of intense investigation for nearly two decades. Over this period, considerable progress has been made in determining the function and regulation of NF-kappaB, although there are nuances in this important signaling pathway that still remain to be understood. The challenge now is to reconcile the regulatory complexity in this pathway with the complexity of responses in which NF-kappaB family members play important roles. In this review, we provide an overview of established NF-kappaB signaling pathways with focus on the current state of research into the mechanisms that regulate IKK activation and NF-kappaB transcriptional activity.

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Signaling to NF-kappaB.

The nuclear factor-kappaB (NF-kappaB)/REL family of transcription factors has a central role in coordinating the expression of a wide variety of genes that control immune responses. There has been intense scientific activity in the NF-kappaB field owing to the involvement of these factors in the activation and regulation of key molecules that are associated with diseases ranging from inflammation to cancer. In this review, we focus on our current understanding of NF-kappaB regulation and its role in the immune system and inflammatory diseases. We also discuss the role of NF-kappaB proteins as potential therapeutic targets in clinical applications.

NF-kappaB regulation in the immune system.

Activation of the NF-κB/Rel transcription family, by nuclear translocation of cytoplasmic complexes, plays a central role in inflammation through its ability to induce transcription of proinflammatory genes (1). This pathway is activated upon appropriate cellular stimulation, most often by signals related to pathogens or stress. Here we will discuss the specificity of various NF-κB proteins, their role in inflammatory disease, the regulation of NF-κB activity by IκB proteins and IκB kinase (IKK), and the development of therapeutic strategies aimed at inhibition of NF-κB.

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NF-κB: a key role in inflammatory diseases

The oligomeric IκB kinase (IKK) is composed of three polypeptides: IKKα and IKKβ, the catalytic subunits, and IKKγ, a regulatory subunit. IKKα and IKKβ are similar in structure and thought to have similar function—phosphorylation of the IκB inhibitors in response to proinflammatory stimuli. Such phosphorylation leads to degradation of IκB and activation of nuclear factor κB transcription factors. The physiological function of these protein kinases was explored by analysis of IKKα-deficient mice. IKKα was not required for activation of IKK and degradation of IκB by proinflammatory stimuli. Instead, loss of IKKα interfered with multiple morphogenetic events, including limb and skeletal patterning and proliferation and differentiation of epidermal keratinocytes.

https://science.sciencemag.org/content/sci/284/5412/316.full.pdf

Abnormal Morphogenesis But Intact IKK Activation in Mice Lacking the IKKα Subunit of IκB Kinase

Interleukin-1 (IL-1) and tumor necrosis factor (TNF-alpha) stimulate transcription factors AP-1 and NF-kappaB through activation of the MAP kinases JNK and p38 and the IkappaB kinase (IKK), respectively. The TNF-alpha and IL-1 signals are transduced through TRAF2 and TRAF6, respectively. Overexpressed TRAF2 or TRAF6 activate JNK, p38, or IKK in the absence of extracellular stimulation. By replacing the carboxy-terminal TRAF domain of TRAF2 and TRAF6 with repeats of the immunophilin FKBP12, we demonstrate that their effector domains are composed of their amino-terminal Zn and RING fingers. Oligomerization of the TRAF2 effector domain results in specific binding to MEKK1, a protein kinase capable of JNK, p38, and IKK activation, and induction of TNF-alpha and IL-1 responsive genes. TNF-alpha also enhances the binding of native TRAF2 to MEKK1 and stimulates the kinase activity of the latter. Thus, TNF-alpha and IL-1 signaling is based on oligomerization of TRAF2 and TRAF6 leading to activation of effector kinases.

/pdf/signaling-by-proinflammatory-cytokines-oligomerization-of-437il24514.pdf

Signaling by proinflammatory cytokines: oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an amino-terminal effector domain.

The GTPases Rac and Cdc42Hs control diverse cellular functions. In addition to being mediators of intracellular signaling cascades, they have important roles in cell morphogenesis and mitogenesis. We have identified a novel PAK-related kinase, PAK4, as a new effector molecule for Cdc42Hs. PAK4 interacts only with the activated form of Cdc42Hs through its GTPase-binding domain (GBD). Co-expression of PAK4 and the constitutively active Cdc42HsV12 causes the redistribution of PAK4 to the brefeldin A-sensitive compartment of the Golgi membrane and the subsequent induction of filopodia and actin polymerization. Importantly, the reorganization of the actin cytoskeleton is dependent on PAK4 kinase activity and on its interaction with Cdc42Hs. Thus, unlike other members of the PAK family, PAK4 provides a novel link between Cdc42Hs and the actin cytoskeleton. The cellular locations of PAK4 and Cdc42Hs suggest a role for the Golgi in cell morphogenesis.

https://www.embopress.org/doi/pdf/10.1093/emboj/17.22.6527

PAK4, a novel effector for Cdc42Hs, is implicated in the reorganization of the actin cytoskeleton and in the formation of filopodia

The IKKalpha and IKKbeta catalytic subunits of IkappaB kinase (IKK) share 51% amino-acid identity and similar biochemical activities: they both phosphorylate IkappaB proteins at serines that trigger their degradation. IKKalpha and IKKbeta differ, however, in their physiological functions. IKKbeta and the IKKgamma/NEMO regulatory subunit are required for activating NF-kappaB by pro-inflammatory stimuli and preventing apoptosis induced by tumour necrosis factor-alpha (refs 5,6,7,8,9,10,11). IKKalpha is dispensable for these functions, but is essential for developing the epidermis and its derivatives. The mammalian epidermis is composed of the basal, spinous, granular and cornified layers. Only basal keratinocytes can proliferate and give rise to differentiated derivatives, which on full maturation undergo enucleation to generate the cornified layer. Curiously, keratinocyte-specific inhibition of NF-kappaB, as in Ikkalpha-/- mice, results in epidermal thickening but does not block terminal differentiation. It has been proposed that the epidermal defect in Ikkalpha-/- mice may be due to the failed activation of NF-kappaB. Here we show that the unique function of IKKalpha in control of keratinocyte differentiation is not exerted through its IkappaB kinase activity or through NF-kappaB. Instead, IKKalpha controls production of a soluble factor that induces keratinocyte differentiation.

Véronique Baud

Papers

Abnormal Morphogenesis But Intact IKK Activation in Mice Lacking the IKKα Subunit of IκB Kinase

Signaling by proinflammatory cytokines: oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an amino-terminal effector domain.

PAK4, a novel effector for Cdc42Hs, is implicated in the reorganization of the actin cytoskeleton and in the formation of filopodia

IKKα controls formation of the epidermis independently of NF-κB

IKKβ Is Essential for Protecting T Cells from TNFα-Induced Apoptosis