MAP3K7 (TAK1) review notes

Provenance / process

2026-10-05: de-novo review. GOA (223 rows), UniProt and stub YAML fetched earlier; publications cached with
just fetch-gene-pmids human MAP3K7 (57/57). Extra PMIDs cached with just fetch-pmid:
8533096 (TAK1 discovery), 14633987 (TAB3), 15327770 (TAB2/TAB3 K63-Ub binding).
Deep research: the falcon provider is known to fail for this batch (HTTP 402), so it was not attempted.
No -deep-research-*.md file exists for this gene; these notes are built from cached primary literature,
the UniProt record and the PTHR46716 family review.
Most key TAK1 papers are cached abstract-only (full_text_available: false): 8663074, 9079627, 10094049,
10702308, 10838074, 10882101, 11460167, 8638164. Full text available for 11865055, 12242293, 12589052,
14982987, 17079228, 17158449, 19675569, 20538596, 21512573, 25371197, 27426733 and several proteomics screens.

MAP3K7 / TAK1, 606 aa (isoform 1B is canonical; 4 splice isoforms), TKL-group Ser/Thr kinase; N-terminal
kinase domain (catalytic K63, HRD D156), C-terminal TAB2/TAB3-binding region (residues ~479-553)
PMID:17158449.
Discovered in a yeast MAPK-pathway complementation screen as a MAPKKK stimulated by TGF-beta and BMP
PMID:8533096.

Phosphorylates and activates MKK6 and MKK3 (p38 branch)
PMID:8663074.
Activates MKK4/SEK1 -> JNK; activated by ceramide
PMID:9079627.
TAK1 complex (TRIKA2 = TAK1+TAB1+TAB2) phosphorylates IKK (IKKbeta) and MKK6 in a K63-ubiquitin-dependent way
PMID:11460167.
Activation is by autophosphorylation in the activation loop (Ser192; Thr184/Thr187)
PMID:10702308;
PMID:10838074.
Inactivated by PP6 dephosphorylation of Thr187 PMID:17079228.
Other direct substrates: AMPK (in vitro) PMID:20538596, STING Ser355 PMID:37832545,
Ror2 C-terminus PMID:18762249. The 1999 claim that TAK1 phosphorylates NIK PMID:10094049 predates the
TAK1->IKKbeta model; NIK is now understood as the non-canonical NF-kB kinase acting independently of TAK1.

TAB1 is a constitutive activator PMID:8638164.
TAB2 links TAK1 to TRAF6 in IL-1 signaling PMID:10882101.
TAB3 is redundant with TAB2 in IL-1 and TNF signaling PMID:14633987.
TAB2/TAB3 NZF domains are K63-polyubiquitin receptors; TAB2 binds ubiquitinated RIP after TNF
PMID:15327770.
Unanchored K63 chains directly activate TAK1 via TAB2 PMID:19675569.
GO term GO:0097076 (TGF-beta activated kinase 1 complex) exists, is unrestricted, but has zero annotations in GOA
(QuickGO, 2026-10-05). ComplexPortal annotates MAP3K7 to the generic GO:1902554 serine/threonine protein kinase
complex (IPI, PMID:22158122). GO:0097076 is_a GO:1902911 protein kinase complex, but NOT is_a GO:1902554
(ontology placement gap). Proposed as NEW (part_of GO:0097076) in this review.

IL-1R/TLR (MyD88-IRAK-TRAF6) [PMID:10094049; PMID:12242293 membrane complex II then cytosolic activation].
TLR3/TRIF -> TRAF6-TAK1-TAB2 -> NF-kB, not IRF3 PMID:14982987.
TLR4 (ECSIT complex) PMID:25371197. TNF via TAB2/TAB3 binding to ubiquitinated RIP1 [PMID:15327770, PMID:14633987].
TGF-beta: TbetaRI-TRAF6 activates TAK1 (K63-Ub of TAK1 Lys34) -> p38/JNK PMID:18758450; TGF-beta-induced apoptosis via TAK1-MKK3-p38 PMID:12589052.
TCR: BCL10-MALT1-TRAF6-TAK1 -> IKK, IL-2 PMID:15125833.
NOD2 PMID:15075345, TRIM5 capsid sensing via free K63 chains PMID:21512573, STING trafficking PMID:37832545.

Frontometaphyseal dysplasia 2 / cardiospondylocarpofacial syndrome: MAP3K7 gain-of-function (P485L)
PMID:27426733.

Core MF: GO:0004709 MAP3K activity and GO:0004674 Ser/Thr kinase (IKKbeta, MKK3/4/6/7). GO:0106310 rows accepted.
GO:0004707 MAP kinase activity (IDA, PMID:11865055): full text shows JNK1 activity was assayed, not TAK1 as a MAPK ->
MODIFY to GO:0004709.
GO:0008349 MAP4K activity (Reactome TAS, mouse IEA): Reactome events are TAK1 autophosphorylation; this is not
MAP4K activity on a distinct MAP3K -> MODIFY to GO:0004674 (autophosphorylation captured by the Ser/Thr kinase term).
54 protein-binding IPI rows: REMOVE (uninformative) except MODIFY where a specific partner class is clear
(E3 ligases -> GO:0031625; PPP6C -> GO:0019903; JIP1 -> GO:0097110; TGFBR1 -> GO:0034713).
Downstream physiology (osteoblast, bone development, hypoxia, angiotensin, vascular SMC, cell size, cell cycle, ROS)
from rat/mouse orthology IEA: MARK_AS_OVER_ANNOTATED or KEEP_AS_NON_CORE.
histone kinase activity / chromatin remodeling IEA (rat): no human evidence; MARK_AS_OVER_ANNOTATED.

Neither modules/tnf_signaling.yaml nor modules/nlr_signaling.yaml has a MAP3K7/TAK1 part, although both modules'
falcon deep research names TAK1-TAB2/3 as the kinase relaying K63/M1-ubiquitin scaffolds to IKKbeta and MAPKs.
The tnf "NF-kappaB and inflammatory output" step is carried by a "TRAF2 signal relay" part, and nlr by
"RIPK2 inflammatory signal relay"; neither is the kinase that phosphorylates IKKbeta. Discrepancy reported to caller.