NFKB p105, TPL2 (COT) and ABIN2 form a stable complex

Stable Identifier
Reaction [binding]
Homo sapiens
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Degradation of NFKB p105 frees Tpl2 from p105 allowing it to activate MEK1.

The C-terminal half of NFKB1 p105 forms a high-affinity stoichiometric association with MAP3K8 (TPL2) via two distinct interactions (Belich et al. 1999; Beinke et al. 2003). The Tpl2 C-terminus (residues 398-467) binds to a region N-terminal to the p105 ankyrin repeat region (human p105 residues 497-534), whereas the Tpl2 kinase domain interacts with the p105 death domain (Beinke et al. 2003). In unstimulated macrophages, all detectable Tpl2 is associated with p105 (Belich et al. 1999; Lang et al. 2004). Binding to p105 maintains the stability of Tpl2 but inhibits Tpl2 MEK kinase activity by preventing access to MEK (Beinke et al. 2003; Waterfield et al. 2003). Tpl2 phosphorylation at Thr-290 may also play a role in the activation of Tpl2 (Cho & Tsichlis 2005).

A20-binding inhibitor of NFkappaB2 (ABIN-2 ot TNIP2) interacts with Tpl2 and p105 but preferentially forms a ternary complex with both proteins. As ABIN2 is a polyubiquitin binding protein, it has been suggested that it may facilitate recruitment of the p105/Tpl2 complex to the activated IKK complex, allowing IKK2 induced p105 phosphorylation and consequent Tpl2 activation.

Literature References
PubMed ID Title Journal Year
12832462 NF-kappaB1 p105 negatively regulates TPL-2 MEK kinase activity

Belich, MP, Ley, SC, Gamblin, SJ, Beinke, S, Smerdon, SJ, Walker, PA, Lang, V, Deka, J, Howell, S

Mol Cell Biol 2003
9950430 TPL-2 kinase regulates the proteolysis of the NF-kappaB-inhibitory protein NF-kappaB1 p105

Belich, MP, Ley, SC, Salmeron, A, Johnston, LH

Nature 1999
15169888 ABIN-2 forms a ternary complex with TPL-2 and NF-kappa B1 p105 and is essential for TPL-2 protein stability

Ley, SC, Symons, A, Janzen, J, Beinke, S, Watton, SJ, Lang, V, Soneji, Y, Howell, S

Mol Cell Biol 2004
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