Activation of IKK by MEKK1

Stable Identifier
R-HSA-933530
Type
Reaction
Species
Homo sapiens
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In Human, IKKs - IkB kinase (IKK) complex serves as the master regulator for the activation of NF-kB by various stimuli. It contains two catalytic subunits, IKK alpha and IKK beta, and a regulatory subunit, IKKgamma/NEMO. The activation of IKK complex and NFkB mediated antiviral responce are dependent on the phosphorylation of IKK alpha/beta at its activation loop and the ubiquitination of NEMO.[Solt et al 2009]; [Li et al 2002]. NEMO ubiquitination by TRAF6 is required for optimal activation of IKKalpha/beta; it's remained unclear if NEMO subunit undergoes K63-linked or linear ubiquitination.

This basic trimolecular complex is referred to as the IKK complex. Each catalytic IKK subunit has a N-term kinase domain a leucine zipper (LZ) motifs, a helix-loop-helix (HLH) and a C-ter NEMO binding domain (NBD). IKK catalytic subunits are dimerized through their LZ motifs.

IKK beta is the major IKK catalytic subunit for NF-kB activation. MEKK1 can activate both IKK-alpha (IKKA) and IKK-beta (IKKB) in vivo. MEKK1 phosphorylates Ser-176 and Ser-180 in IKKA and Ser-177 and Ser-181 in IKKB activation loop and thus activate the IKK kinase activity, leading to the IkB alpha phosphorylation and NF-kB activation.

Literature References
PubMed ID Title Journal Year
9689078 MEKK1 activates both IkappaB kinase alpha and IkappaB kinase beta

Lee, FS, Peters, RT, Dang, LC, Maniatis, T

Proc Natl Acad Sci U S A 1998
12221085 IKKalpha, IKKbeta, and NEMO/IKKgamma are each required for the NF-kappa B-mediated inflammatory response program

Li, X, Massa, PE, Hanidu, A, Peet, GW, Aro, P, Savitt, A, Mische, S, Li, J, Marcu, KB

J Biol Chem 2002
19666475 The nemo binding domains of both IKKalpha and IKKbeta regulate IKK complex assembly and classical NFkappaB activation

Solt, LA, Madge, LA, May, MJ

J Biol Chem 2009
9008162 Activation of the IkappaB alpha kinase complex by MEKK1, a kinase of the JNK pathway

Lee, FS, Hagler, J, Chen, ZJ, Maniatis, T

Cell 1997
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Title
MAP kinase kinase kinase activity of dsRNA:RIG-I/MDA5:IPS-1:TRAF2/TRAF6:MEKK1 [mitochondrial outer membrane]
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