Phosphorylation of IKKs complex mediated by MEKK1

Stable Identifier
R-GGA-1227783
Type
Reaction
Species
Gallus gallus
Compartment
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Summation

The 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 the NFkB mediated antiviral response are dependent on the phosphorylation of IKK alpha/beta at its activation loop and the K63-linked ubiquitination of NEMO[Solt et al 2009; Li et al 2002]. NEMO ubiquitination by TRAF6 is required for optimal activation of IKKalpha/beta. This basic trimolecular complex is referred to as the IKK complex.

Each catalytic IKK subunit has an N-terminus kinase domain, a leucine zipper (LZ) motif, a helix-loop-helix (HLH) and a C-terminus 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. Phosphorylation in the activation loop of IKK beta requires Ser177 and Ser181 (data for human proteins) and thus activates the IKK kinase activity, leading to the IkB alpha phosphorylation and NF-kB activation.

Chicken IKK alpha and IKK beta showed 81% and 68% identity to the corresponding human IKK kinases (UniProtKB sequence data using NCBI BLASTP 2.2.20). Multiple sequence alignment of the proteins by ClustalW demonstrated that chicken IKK alpha serine residues 190 and 194 correspond to human Ser176 and Ser180, that are required for the activation. It is unclear what serine residues of chicken IKK beta are involved into the phosphorylation.

Chicken IKK gamma or NEMO is considered as avian lost.[Cormican et al 2009].

MEKK1 can activate both IKK-alpha and IKK-beta in vivo[Lee FS et al 1998]. IKKs are activated through phosphorylation of Ser-176 & Ser-180 in IKKA and Ser-177 & Ser-181 in IKKB in their activation loops, leading to the IkB alpha phosphorylation and NF-kB activation [Ling L et al 1998, Delhase M et al 1999, Kamata H et al 2002]

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Catalyst Activity
Title
protein kinase activity of dsRNA:MDA5:IPS1:K63-pUb-TRAF6/or TRAF2:MEKK1 [mitochondrial outer membrane]
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