A taxon-neutral decomposition of the p38 mitogen-activated protein kinase cascade, the stress- and cytokine-activated concrete realization of the generic three-tier MAP kinase relay (MODULE:mapk_relay). Environmental stresses (UV, osmotic and oxidative stress) and inflammatory cytokines (TNF, IL-1) signal through upstream MAP3Ks (ASK1/MAP3K5, TAK1/MAP3K7, MLK family) to the dual-specificity MAP2Ks MKK3 (MAP2K3) and MKK6 (MAP2K6), which dually phosphorylate the p38 MAPKs (p38 alpha/beta/gamma/delta) on their TGY activation-loop motif. Active p38 phosphorylates substrate kinases (MK2/MAPKAPK2) and transcription factors (ATF2, MEF2), driving stress-response and inflammatory gene programs. The RAF-analogous kinase relay - MAP3K -> MKK3/6 -> p38 - is declared as an inner bundle that `conforms_to` mapk_relay, while the stress/cytokine input and the p38 effector output and DUSP-mediated feedback are this cascade's free extensions around the conforming core. Grounded in GO:0038066 (p38MAPK cascade) / GO:0051403 (stress-activated MAPK cascade).
This module is the concrete p38 (stress-activated) branch of the generic three-tier MAP kinase relay (MODULE:mapk_relay): the inner `p38_relay` node bundles the MAP3K -> MKK3/6 -> p38 tiers and declares conformance to that motif, while the stress/cytokine input step and the downstream p38-output and DUSP-feedback steps are this cascade's free extensions around the conforming core. Representative UniProt members (ASK1 Q99683, MKK6 P52564, MKK3 P46734, p38 alpha Q16539) were verified against UniProt. PANTHER grounding: kinase- tier family descriptors carry family-level PTHR ids checked against interpro/panther membership (PTHR24055 for every MAPK tier, PTHR48013 for all MAP2Ks, including MEK1/MEK2, MKK3/4/5/6/7 and Pbs2/Ste7, per the current PANTHER classification, PTHR24361 for MEKK2/MEKK3). PANTHER subfamilies are deliberately not used: they are not clean paralog groups here (e.g. PTHR48013:SF9, named for MEK5, also contains yeast Ste7 and plant MKKs), so branch identity is carried by the representative members and the PTN evidence rather than by a subfamily id. The stress-activated MAP3K descriptor (ASK1/TAK1/MLK) spans unrelated PANTHER families and asserts no id.
All recommended fields populated.
✗ none found
No MODULE:p38_cascade deep-research report alongside the module YAML.
3 leaf node(s) with no concrete protein grounding:
✓ every declared conforms_to bundle matches its template motif.
4 gene-function check(s) reflected in core functions · 0 conflict(s) · 3 evidence or coverage gap(s) (8 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 |
|---|---|---|---|
| p38_map3k_activity | ASK1 (MAP3K5) UniProtKB:Q99683 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). |
| p38_map2k_activity | MKK6 (MAP2K6) UniProtKB:P52564 Family Representative |
MAP kinase kinase activity GO:0004708 |
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass). |
| p38_map2k_activity | MKK3 (MAP2K3) UniProtKB:P46734 Family Representative |
MAP kinase kinase activity GO:0004708 |
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass). |
| p38_mapk_activity | MAPK14 (p38 alpha) UniProtKB:Q16539 Family Representative |
MAP kinase activity GO:0004707 |
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass). |
| p38_substrate_output | ANY_WITH_FUNCTION Gene |
MAP kinase activity GO:0004707 |
Participant Unchecked
No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews. |
| p38_map3k_activity | Stress-activated MAP3Ks (ASK1/TAK1/MLK) Family |
MAP kinase kinase kinase activity GO:0004709 |
Family Id Missing
The family has no identifier linking it to a curated family review. |
| p38_map2k_activity | MKK3/MKK6 (MAP2K3/MAP2K6) PANTHER:PTHR48013 Family |
MAP kinase kinase activity GO:0004708 |
Family Review Missing
No supported structured family review is available for PANTHER:PTHR48013. |
| p38_mapk_activity | p38 MAPKs (MAPK14/11/12/13) PANTHER:PTHR24055 Family |
MAP kinase activity GO:0004707 |
Family Function Unreviewed
Family review leaves GO:0004707 UNRESOLVED. The cucumber target has a MAP-kinase conserved-site signature, supporting MAPK-type phosphotransfer rather than an arbitrary kinase label. Classical MAPKs and divergent CMGC relatives nevertheless differ in activation-loop regulation and upstream kinases. The complete functional boundary cannot be inferred from a rule-generated catalytic equation or extended to every CMGC-like member without catalytic and activation-mechanism evidence. |
✓ every negative regulator described as feedback has an upstream edge closing the loop.
4 complete review(s) · 4 with deep research · 0 missing review · 0 reviewed but lacking deep research
| Gene | Review | Complete | Deep research |
|---|---|---|---|
| MAP2K3 P46734 | ✓ | ✓ | ✓ |
| MAP2K6 P52564 | ✓ | ✓ | ✓ |
| MAP3K5 Q99683 | ✓ | ✓ | ✓ |
| MAPK14 Q16539 | ✓ | ✓ | ✓ |
Environmental stress (UV, osmotic, oxidative) and inflammatory cytokines (TNF, IL-1), relayed through MAP4Ks, Rho-family GTPases, and adaptor MAP3Ks, converge to activate the MAP3K tier of the cascade.
Couples stress and cytokine stimuli to the p38 relay.
The three-tier kinase relay of the p38 cascade: a stress-activated MAP3K (ASK1/TAK1/MLK) phosphorylates MKK3/MKK6 (MAP2K), which dually phosphorylates p38 (MAPK) on its TGY activation-loop motif.
Stress-activated MAP3Ks (ASK1/MAP3K5, TAK1/MAP3K7, MLK family) phosphorylate and activate MKK3/MKK6.
Top kinase tier; activates MKK3/6.
The dual-specificity MAP2Ks MKK3 (MAP2K3) and MKK6 (MAP2K6) phosphorylate p38 on both threonine and tyrosine of its TGY motif.
Middle kinase tier; dual-specificity activation of p38.
Dually phosphorylated p38 (alpha/beta/gamma/delta) becomes an active proline-directed serine/threonine kinase acting on cytoplasmic and nuclear substrates.
Effector kinase transducing the stress signal to substrates.
Active p38 phosphorylates the substrate kinase MK2 (MAPKAPK2) and the transcription factors ATF2 and MEF2, driving stress-response and inflammatory gene programs and post-transcriptional control of cytokine mRNAs.
Converts p38 activity into a stress/inflammatory gene program.
DUSP/MKP dual-specificity phosphatases (e.g. DUSP1/MKP-1, DUSP10/MKP-5) dephosphorylate the p38 activation loop to terminate signaling, many of them induced by p38 itself as negative feedback.
Dephosphorylates the p38 activation loop to terminate signaling.