TNFR1 signaling kinetics: Spatiotemporal control of three phases of IKK activation by posttranslational modification

• Published in: Cellular signalling Vol. 25; no. 8; pp. 1654 - 1664
• Main Authors: Workman, Lauren M., Habelhah, Hasem
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01.08.2013
• Subjects: Activation; Animals; CASP8 and FADD-Like Apoptosis Regulating Protein - metabolism; cIAP1; Cytokines; Humans; I-kappa B Kinase - metabolism; inflammation; Inflammatory response; JNK Mitogen-Activated Protein Kinases - metabolism; Kinases; NF-kappa B - metabolism; NF-κB; Nuclear Pore Complex Proteins - metabolism; Pathways; Phases; Protein Processing, Post-Translational; protein-serine-threonine kinases; Reactive Oxygen Species - metabolism; Receptors, Tumor Necrosis Factor, Type I - chemistry; Receptors, Tumor Necrosis Factor, Type I - metabolism; RIP1; RNA-Binding Proteins - metabolism; serine; Signal Transduction; Strategy; Three phase; threonine; TNF Receptor-Associated Factor 2 - genetics; TNF Receptor-Associated Factor 2 - metabolism; TNFα; TRAF2; transcription factor NF-kappa B; tumor necrosis factor-alpha; ubiquitination; TNFα; cFLIP; TRAF; JNK; TRADD; cIAP1; TNF; IκB; NF-κB; S1P; TBK1; TAK1; DICS; UBD; SM; FADD; MEFs; TNFR; KO; MEKK1; IL-1; ASK1; IKK; DKO; TRAF2; LUBAC; IL-6; RA; NIK; ROS; TAB1; RIP1
• ISSN: 0898-6568; 1873-3913; 1873-3913
• DOI: 10.1016/j.cellsig.2013.04.005

TNFα is a pleotropic cytokine that plays a central role in the inflammatory response by activating the NF-κB signaling pathway, and is targeted in a range of chronic inflammatory diseases, underscoring the therapeutic importance of understanding its underlying molecular mechanisms. Although K63-linked ubiquitination of RIP1 by TRAF2/5 and cIAP1/2 was thought to serve as a scaffold to activate the NF-κB pathway, the recent accumulation of conflicting results has challenged the necessity of these proteins in NF-κB activation. In addition, several serine/threonine kinases have been implicated in TNFα-induced IKK activation; however, the targeted disruption of these kinases had no effect on transient IKK activation. The recent discovery of RIP1-dependent and -independent activation of the early and delayed phases of IKK and TRAF2 phosphorylation-dependent activation of the prolonged phase of IKK offers a reconciliatory model for the interpretation of contradictory results in the field. Notably, the TNFα-induced inflammatory response is not exclusively controlled by the NF-κB pathway but is subject to regulatory crosstalk between NF-κB and other context-dependent pathways. Thus further elucidation of these spatiotemporally-coordinated signaling mechanisms has the potential to provide novel molecular targets and therapeutic strategies for NF-κB intervention.