Transforming growth factor-β-activated kinase 1 (TAK1) is a central regulator of cell death and is activated through a diverse set of intra- and extracellular stimuli. The kinase TAK1 was first identified as a mitogen-activated protein kinase kinase kinase (MAP3K) and found to be activated by TGFβ and bone morphologic protein. Since this original finding, TAK1 also has been shown to be activated by a number of signaling molecules including cytokines such as TNFα and IL-1; ligands that interact with Toll-like receptors, B-cell receptor and T-cell receptor; and the lipotoxic molecule, ceramide. Other endogenous death ligands of the TNF family, including TRAIL, also induce TAK1 activation.Exogenous stressors and environmental changes such as osmotic stress, UV irradiation, ischemia and nutrient withdrawal activate TAK1. 
Upon TNFα stimulation, adaptor molecules including TNFα receptor type-1-associated death domain protein (TRADD), TNFα receptor-associated factor 2 and 5 (TRAF2 and TRAF5), cellular inhibitor of apoptosis 1 and 2 (cIAP1/2) and RIPK1 are recruited to the receptor complex (TNF receptor 1 (TNFR1) Complex I), in which RIPK1 acquires a K63-linked or linear polyubiquitin chain by E3 ligases, TRAF2/5 cIAP1/2 or linear ubiquitin chain assembly complex containing two E3 ligases HOIL-1 and HOIP. TAK1 is recruited and activated through TAK1-binding protein 2 (TAB2) binding to the RIPK1 polyubiquitin chain.23, 24 Upon binding the polyubiquitin chain, TAK1 phosphorylates and activates the IKK complex composed of IKKα, IKKβ and NEMO (also called IKKγ), which leads to phosphorylation and degradation of IκB resulting in activation of NF-κB. Activated TAK1 also phosphorylates and activates MAPKKs leading to activation of MAPKs such as ERK, p38 and JNK. NF-κB and MAPKs induce downstream expression of inflammatory cytokines and antiapoptotic proteins such as cellular FLICE-like inhibitory protein (c-FLIP) and cIAPs. Drawing a link between TAK1 signaling and metabolism, studies have found that starvation and TRAIL induce autophagy in which TAK1 is actively involved by activating AMP-activated protein kinase and IKKs.


1.S R Mihaly,et al. Cell Death Differ. 2014 Nov; 21(11): 1667–1676.