TAK1TAB

TAK1TAB refers to the signaling module formed by TAK1 (MAP3K7) and its TAK1-binding proteins, TAB1 (MAP3K7IP1), TAB2 (MAP3K7IP2), and TAB3 (MAP3K7IP3). The TAK1TAB complex plays a central role in transducing signals from innate immune receptors such as IL-1, TNF, Toll-like receptors and other pattern-recognition pathways, leading to activation of inflammatory transcription programs.

In unstimulated cells TAK1 forms complexes with TAB proteins, and upon receptor engagement TAB2 and TAB3 recognize and bind K63-linked polyubiquitin chains generated at signaling hubs. This ubiquitin-dependent recruitment brings TAK1 into proximity with upstream kinases and adaptor proteins. TAB1 is particularly important for activating TAK1’s kinase activity, promoting autophosphorylation and full signal propagation. Activated TAK1 then phosphorylates downstream targets, including the IKK complex (leading to NF-κB activation) and MAP kinase cascades (p38, JNK, and sometimes ERK), culminating in the expression of inflammatory and immune-response genes.

Structure and regulation: TAB1 contains a TAK1-binding region and domains that support TAK1 activation, while TAB2 and TAB3 contain NZF ubiquitin-binding domains that facilitate association with polyubiquitinated signaling complexes. The activity of the TAK1TAB module is modulated by ubiquitination dynamics and deubiquitinating enzymes such as CYLD and A20, which provide negative feedback to limit signaling.

Clinical relevance: Dysregulation of the TAK1TAB module has been linked to inflammatory diseases and certain cancers. Because TAK1 signaling influences NF-κB and MAPK pathways, the TAK1TAB complex remains a focus for therapeutic strategies aiming to modulate excessive inflammatory responses.