A compact canonical NF-kappaB module. Pro-inflammatory receptors such as TNFR1 assemble adaptor/ubiquitin ligase complexes, activate the IKK complex, induce phosphorylation and proteasomal destruction of IkappaB inhibitors, and release NF-kappaB dimers to enter the nucleus and drive inflammatory, survival, and immune-response genes. The module is grounded in GO:0007249 and includes curated TNFR1, TRAF2, TAK1-TAB, IKK, IkappaB, and NF-kappaB exemplars, with PTN anchors where PAINT seed rows support the role.
TAK1 step (2026-10-06): the TAK1-TAB complex (MAP3K7 with TAB1 and TAB2/TAB3) was added as the IKKbeta-activating kinase step between the receptor-proximal ubiquitin scaffold and IKK activation, matching the tak1_tab_kinase_activation part in MODULE:tnf_signaling and MODULE:nlr_signaling and the MAP3K7 gene review. Before this, the receptor/TRAF tier was linked directly to IKK, which omitted the kinase that phosphorylates the IKKbeta activation loop. Only the IKKbeta-directed (GO:0004674) activity of TAK1 is modelled here; its MAP3K (GO:0004709) activity toward p38/JNK MAP2Ks is outside this module and is modelled in the TNF and NLR modules.
All recommended fields populated.
✗ none found
No MODULE:nfkb_canonical_signaling deep-research report alongside the module YAML.
✓ every leaf node grounds to a representative protein.
✓ every declared conforms_to bundle matches its template motif.
2 gene-function check(s) reflected in core functions · 0 conflict(s) · 4 evidence or coverage gap(s) (7 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 |
|---|---|---|---|
| tnfr1_receptor | TNFRSF1A UniProtKB:P19438 Family Representative |
tumor necrosis factor receptor activity GO:0005031 |
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass). |
| 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. |
| ikk_kinase | CHUK UniProtKB:O15111 Family Representative |
protein serine/threonine kinase activity GO:0004674 |
Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked. |
| ikk_kinase | IKBKB UniProtKB:O14920 Family Representative |
protein serine/threonine kinase activity GO:0004674 |
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass). |
| tnfr1_receptor | TNFRSF1A receptor family PANTHER:PTHR46861 Family |
tumor necrosis factor receptor activity GO:0005031 |
Family Review Missing
No supported structured family review is available for PANTHER:PTHR46861. |
| ikk_kinase | IkappaB kinase family PANTHER:PTHR22969 Family |
protein serine/threonine kinase activity GO:0004674 |
Family Function Unreviewed
The family review has no applicable adjudication supporting or excluding GO:0004674. |
1 complete review(s) · 2 with deep research · 6 missing review · 2 reviewed but lacking deep research
| Gene | Review | Complete | Deep research |
|---|---|---|---|
| IKBKB O14920 | ✓ | ✓ | ✗ |
| MAP3K7 O43318 | ✓ | 223/224 | ✗ |
| CHUK O15111 | ✗ | — | — |
| NFKB1 P19838 | ✗ | — | — |
| NFKBIA P25963 | ✗ | — | — |
| RELA Q04206 | ✗ | — | — |
| TAB1 Q15750 | ✗ | — | — |
| TAB2 Q9NYJ8 | ✗ | — | — |
| TNFRSF1A P19438 | ✓ | 144/146 | ✓ |
| TRAF2 Q12933 | ✓ | 702/708 | ✓ |
Ligand-bound TNFR-family receptors recruit adaptor proteins and TRAF ubiquitin ligases that build ubiquitin scaffolds for IKK activation.
Cell-surface receptor exemplar for canonical inflammatory NF-kappaB activation.
Receptor-proximal scaffold/ligase tier that couples TNFR signaling to IKK.
The TAK1-TAB complex (TAK1 kinase with TAB1 and the ubiquitin-binding subunits TAB2/TAB3) binds K63-linked (and unanchored) polyubiquitin chains built by the receptor-proximal TRAF/RIPK/IRAK scaffold through the TAB2/TAB3 Npl4 zinc fingers, and TAK1 is activated. Activated TAK1 phosphorylates the IKKbeta activation loop (Ser177/Ser181), which commits canonical NF-kappaB signaling. NEMO binding to the same K63/M1-linked chains brings IKK to TAK1, and IKKbeta trans-autophosphorylation then amplifies IKK activity (step 3). TRAFs and RIPK1 provide the docking platform and do not phosphorylate IKK themselves.
Ubiquitin-activated TAK1 complex phosphorylates and activates IKKbeta, the upstream kinase step of the canonical cascade.
NEMO/IKKgamma-bound IKK alpha and IKK beta are activated and phosphorylate IkappaB inhibitors, marking them for ubiquitin-dependent degradation.
Catalytic kinase tier that commits the canonical cascade.
Cytosolic inhibitor degraded after IKK phosphorylation.
Degradation of IkappaB exposes nuclear localization signals on NF-kappaB dimers such as p50/RELA, allowing nuclear import and target gene activation.
Transcription factor output of the canonical pathway.