The essential role of MEKK3 in TNF-induced NF-κB activation

Abstract

Activation of IkappaB kinase (IKK) is the key step in stimulation of the transcription factor NF-kappaB, which regulates many genes in the inflammatory response pathway. The molecular mechanism that underlies IKK activation in response to tumor necrosis factor (TNF) is still unknown. Using mitogen-activated protein kinase kinase kinase 3 (MEKK3)-deficient fibroblast cells, we found that MEKK3 plays a critical role in TNF-induced NF-kappaB activation. We have shown that MEKK3 is required for IKK activation and functions downstream of receptor-interacting protein (RIP) and TNF receptor- associated factor 2. We have also shown that MEKK3 interacts with RIP and directly phosphorylates IKK. The kinase activity of MEKK3 is pivotal to its function and, therefore, MEKK3 links RIP and IKK in TNF-induced NF-kappaB activation.

The C-terminal Activating Region 2 of the Epstein-Barr Virus-encoded Latent Membrane Protein 1 Activates NF-κB through TRAF6 and TAK1

“…Subsequent studies in cells derived from knock-out mice do not support a critical role for these kinases in NF-B activation (11,54). For MEKK3, studies based on MEKK3 knock-out mice show that it is required for both the TNF␣ and IL-1␤-mediated NF-B activation (56,57). It remains to be seen whether MEKK3 also plays a role in the LMP1-mediated NF-B pathway.…”

New insights into the biogenesis of nuclear RNA polymerases?This paper is one of a selection of papers published in this special issue entitled “Canadian Society of Biochemistry, Molecular & Cellular Biology 52nd Annual Meeting — Protein Folding: Principles and Diseases” and has undergone the Journal's usual peer review process.

“…In accordance to this general scheme, MEKK3 is known to phosphorylate a number of MAP(2)K (MEK/MKK1-7), which leads to the activation of their specific downstream MAPK (ERK1/2, JNK/SAPK, ERK5, and p38) (Blank et al 1996;Deacon and Blank 1997;Ellinger-Ziegelbauer et al 1997;Chao et al 1999;Deacon and Blank 1999;Uhlik et al 2003). MEKK3 is also involved in the NF-κB pathway where it activates the IKK complex in response to TNFα and LPS (Yang et al 2001;Schmidt et al 2003;Samanta et al 2004). …”

Interleukin-1 (IL-1)-induced TAK1-dependent Versus MEKK3-dependent NFκB Activation Pathways Bifurcate at IL-1 Receptor-associated Kinase Modification

“…Once activated, TAK1 leads to the phosphorylation of IKK␤ and MKK6, resulting in the activation of both the JNK and NFB signaling pathways. In addition to TAK1, MEKK2 and MEKK3 have also been implicated in the activation of IKK and MAPK, leading to the activation of NFB and JNK (25)(26)(27)(28). The detailed signaling mechanism is not clear.…”

“…Antibodies against ubiquitin, NFB, IRAK, and TAK1 were from Santa Cruz Biotechnology. 293 and IRAK-deficient cells (11), TAK1-deficient MEFs (29), MEKK3-deficient MEFs (26), and IKK␣ (31), IKK␤ (32,33), and IKK␣/␤-deficient MEFs (34) were maintained in Dulbecco's modified Eagle's medium, supplemented with 10% fetal bovine serum, penicillin G (100 g/ml), and streptomycin (100 g/ml).…”