TNF binding to TNF receptor complexes nucleates TRADD, RIPK, and TRAF signaling assemblies that balance NF-kappaB activation, inflammatory gene expression, survival, and death decisions.
Curated compact signaling-pathway module generated from verified UniProt exemplar accessions and local PAINT IBD rows. PTN anchors are included only when the exemplar accession appears in an IBD seed row in interpro/panther; roles without local PAINT seeds remain grounded by verified UniProt exemplar accessions. Falcon integration (2026-06-28): Falcon findings are linked as evidence and family-level support. Automatically extracted open-question headings were intentionally not retained as knowledge_gap entries because they were not manually curated. Machine-generated Falcon citations remain curation support and are not manually adjudicated here. TAK1 step (2026-10-06): the TAK1-TAB complex (MAP3K7 with TAB1 and TAB2/TAB3) was added as the kinase step between the complex I ubiquitin scaffold and the NF-kappaB/MAPK output, following the MAP3K7 gene review and the module's own deep research. Before this, the output was linked directly to the adaptor step through a TRAF2 "signal relay", which implied TRAF2 performs a kinase step it lacks. TAB1/TAB2/TAB3 are active units of a GO:0097076 complex participant because none has a gene review here. The IKK complex (CHUK/IKBKB/IKBKG) remains outside this module; it is modeled in MODULE:nfkb_canonical_signaling.
All recommended fields populated.
✓ present
✓ every leaf node grounds to a representative protein.
✓ every declared conforms_to bundle matches its template motif.
1 gene-function check(s) reflected in core functions · 0 conflict(s) · 1 evidence or coverage gap(s) (4 comparison(s))
Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.
| Annoton | Participant | Function | Assessment |
|---|---|---|---|
| tak1_complex_ikkbeta_kinase | PROTEIN_COMPLEX Gene |
protein serine/threonine kinase activity (IKKbeta activation loop) GO:0004674 |
Participant Unchecked
No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews. |
| tak1_complex_ikkbeta_kinase/tab2_tab3_ubiquitin_receptor | TAB2 UniProtKB:Q9NYJ8 Complex Unit |
K63-linked polyubiquitin modification-dependent protein binding GO:0070530 |
Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked. |
| tak1_map3k | MAP3K7 UniProtKB:O43318 Family Representative |
MAP kinase kinase kinase activity GO:0004709 |
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass). |
| tak1_map3k | TAK1/MAP3K7 ortholog group PANTHER:PTHR46716:SF1 Family |
MAP kinase kinase kinase activity GO:0004709 |
Family Supported
Family review supports GO:0004709 for PANTHER:PTHR46716:SF1. MAP3K activity defines the bilaterian TAK1 clade. TAK1 phosphorylates MKK3, MKK6 and MKK4, and fly Tak1 is the MAPKKK of the JNK pathway. SF1 is the family's only subfamily, so the scope is stated as SF1. The human MAP3K7 gene review confirms this scoping: it accepts MAP3K activity (IDA on MKK3/MKK6 and MKK4/MKK7) as its core MF and accepts the Bilateria-node IBA. Comparative evidence from outside the PANTHER family agrees: C. elegans MOM-4 (a PTHR23257 leaf in PANTHER 19) phosphorylates the LIT-1 activation-loop Thr220 directly, and the kinase-dead D176N mutant does not. Dictyostelium Phg2, which UniProt/InterPro also cross-reference to SF1 but PANTHER places in PTHR23257:SF776, has no known MAP2K substrate and is outside this scope. |
1 complete review(s) · 2 with deep research · 4 missing review · 3 reviewed but lacking deep research
| Gene | Review | Complete | Deep research |
|---|---|---|---|
| IKBKB O14920 | ✓ | ✓ | ✗ |
| MAP3K7 O43318 | ✓ | 223/224 | ✗ |
| TNF P01375 | ✗ | — | — |
| TRADD Q15628 | ✗ | — | — |
| TAB1 Q15750 | ✗ | — | — |
| TAB2 Q9NYJ8 | ✗ | — | — |
| RIPK1 Q13546 | ✓ | 302/304 | ✗ |
| TNFRSF1A P19438 | ✓ | 144/146 | ✓ |
| TRAF2 Q12933 | ✓ | 702/708 | ✓ |
TNF ligand activates TNFRSF1A/TNFR1 receptor signaling complexes.
Curated exemplar for the tnf ligand role in tumor necrosis factor-mediated signaling pathway.
Curated exemplar for the tnfr1 receptor role in tumor necrosis factor-mediated signaling pathway.
TRADD, RIPK1, and TRAF2 assemble proximal TNFR signaling complexes (complex I). TRAF2 recruits cIAP1/2, which attach K63-linked chains to RIPK1, and LUBAC adds linear chains; these chains are a ubiquitin scaffold, not a kinase step. cIAP1/2 and LUBAC are not modeled as parts here.
Curated exemplar for the tradd adaptor role in tumor necrosis factor-mediated signaling pathway.
Curated exemplar for the ripk1 kinase/scaffold role in tumor necrosis factor-mediated signaling pathway.
Curated exemplar for the traf2 adaptor role in tumor necrosis factor-mediated signaling pathway.
The TAK1-TAB complex (TAK1 kinase with TAB1 and the ubiquitin-binding subunits TAB2/TAB3) is recruited to K63-linked chains on RIPK1 in TNFR1 complex I and activated. Activated TAK1 phosphorylates IKKbeta, which commits canonical NF-kappaB signaling, and the MAP2Ks MKK3/6 and MKK4/7, which drive p38 and JNK signaling. This is the first kinase step after the ubiquitin scaffold. TRAF2 and RIPK1 provide the docking platform and do not phosphorylate IKK themselves.
Ubiquitin-activated TAK1 complex phosphorylates and activates IKKbeta. The IKK complex (IKKalpha/IKKbeta/NEMO) is the downstream output, modeled in the canonical NF-kappaB module rather than here.
The same ubiquitin-activated TAK1 phosphorylates MAP2Ks that feed the p38 and JNK arms of the TNF inflammatory output.
TAK1-activated IKK and MAPK signaling relays TNF input to NF-kappaB and inflammatory programs. The annotons here are receptor-side context for this output. TRAF2 and TNFR1 have no IKK- or MAP2K-directed kinase activity; the kinase step is tak1_tab_kinase_activation.
TRAF2 adaptor/E3 scaffold that sustains cIAP-dependent K63 ubiquitination in complex I. Through that scaffold it couples TNF input to the TAK1-TAB complex. It is not an IKK kinase; NF-kappaB and MAPK output requires TAK1 activity downstream.
Curated exemplar for the tnfr1 pathway context role in tumor necrosis factor-mediated signaling pathway.