Activation of IKK by MEKK1

Stable Identifier
R-HSA-933530
Type
Reaction [transition]
Species
Homo sapiens
Related Species
Influenza A virus, Human respiratory syncytial virus A, Rotavirus, Hepatitis C Virus, Measles virus
Compartment
cytosol, mitochondrial outer membrane
ReviewStatus
5/5
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Activation of IKK by MEKK1
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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
12221085 IKKalpha, IKKbeta, and NEMO/IKKgamma are each required for the NF-kappa B-mediated inflammatory response program

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

J Biol Chem 2002
9689078 MEKK1 activates both IkappaB kinase alpha and IkappaB kinase beta

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

Proc Natl Acad Sci U S A 1998
19666475 The nemo binding domains of both IKKalpha and IKKbeta regulate IKK complex assembly and classical NFkappaB activation

May, MJ, Madge, LA, Solt, LA

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
Participants
Input
Output
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as an event of
Catalyst Activity

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

Physical Entity
dsRNA:DDX58/IFIH1:MAVS:TRAF2/TRAF6:MEKK1 [mitochondrial outer membrane] (Homo sapiens)
Activity
MAP kinase kinase kinase activity (GO:0004709)
Orthologous Events
Phosphorylation of IKKs complex mediated by MEKK1 (Gallus gallus)
Authored
Garapati, P V  (2010-08-02)
Reviewed
Akira, S  (2010-10-30)
Kawai, T  (2010-10-30)
Created
Garapati, P V  (2010-08-16)
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