A taxon-neutral decomposition of the ERK5 (big MAP kinase 1, BMK1) cascade, the MEF2-driven concrete realization of the generic three-tier MAP kinase relay (MODULE:mapk_relay). Growth factors, and oxidative and osmotic stress, signal through the MAP3Ks MEKK2 (MAP3K2) and MEKK3 (MAP3K3) to the dedicated dual-specificity MAP2K MEK5 (MAP2K5), which dually phosphorylates the MAPK ERK5 (MAPK7) on its TEY activation-loop motif. ERK5 is distinctive in carrying a large C-terminal transcriptional-activation domain in addition to its kinase domain, and its principal output is activation of MEF2-family transcription factors controlling proliferation, survival, and endothelial/cardiovascular development. The kinase relay - MEKK2/3 -> MEK5 -> ERK5 - is declared as an inner bundle that `conforms_to` mapk_relay, while the upstream input and the ERK5/MEF2 output are this cascade's free extensions around the conforming core. Grounded in GO:0070375 (ERK5 cascade).
This module is the concrete ERK5 branch of the generic three-tier MAP kinase relay (MODULE:mapk_relay): the inner `erk5_relay` node bundles the MEKK2/3 -> MEK5 -> ERK5 tiers and declares conformance to that motif, while the upstream input and the downstream ERK5/MEF2 output are this cascade's free extensions around the conforming core. Representative UniProt members (MEKK3 Q99759, MEKK2 Q9Y2U5, MEK5 Q13163, ERK5 Q13164) 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.
All recommended fields populated.
✗ none found
No MODULE:erk5_cascade deep-research report alongside the module YAML.
2 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 |
|---|---|---|---|
| erk5_map3k_activity | MEKK3 (MAP3K3) UniProtKB:Q99759 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). |
| erk5_map3k_activity | MEKK2 (MAP3K2) UniProtKB:Q9Y2U5 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). |
| erk5_map2k_activity | MEK5 (MAP2K5) UniProtKB:Q13163 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). |
| erk5_mapk_activity | ERK5 (MAPK7) UniProtKB:Q13164 Family Representative |
MAP kinase activity GO:0004707 |
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass). |
| erk5_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. |
| erk5_map3k_activity | MEKK2/MEKK3 (MAP3K2/MAP3K3) PANTHER:PTHR24361 Family |
MAP kinase kinase kinase activity GO:0004709 |
Family Review Missing
No supported structured family review is available for PANTHER:PTHR24361. |
| erk5_map2k_activity | MEK5 (MAP2K5) PANTHER:PTHR48013 Family |
MAP kinase kinase activity GO:0004708 |
Family Review Missing
No supported structured family review is available for PANTHER:PTHR48013. |
| erk5_mapk_activity | ERK5 (MAPK7) 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. |
2 complete review(s) · 4 with deep research · 0 missing review · 0 reviewed but lacking deep research
| Gene | Review | Complete | Deep research |
|---|---|---|---|
| MAP2K5 Q13163 | ✓ | 72/73 | ✓ |
| MAP3K2 Q9Y2U5 | ✓ | 29/30 | ✓ |
| MAP3K3 Q99759 | ✓ | ✓ | ✓ |
| MAPK7 Q13164 | ✓ | ✓ | ✓ |
Growth factors (EGF, neurotrophins) and oxidative/osmotic stress, relayed through receptor tyrosine kinases and upstream regulators, converge to activate the MEKK2/MEKK3 MAP3K tier of the cascade.
Couples growth-factor and stress stimuli to the ERK5 relay.
The three-tier kinase relay of the ERK5 cascade: MEKK2/MEKK3 (MAP3K) phosphorylate MEK5 (MAP2K), which dually phosphorylates ERK5 (MAPK) on its TEY activation-loop motif.
The MAP3Ks MEKK2 (MAP3K2) and MEKK3 (MAP3K3) phosphorylate and activate MEK5.
Top kinase tier; activates MEK5.
The dual-specificity MAP2K MEK5 (MAP2K5) phosphorylates ERK5 on both threonine and tyrosine of its TEY motif.
Middle kinase tier; dual-specificity activation of ERK5.
Dually phosphorylated ERK5 (MAPK7) becomes an active proline-directed serine/threonine kinase; its large C-terminal domain also provides intrinsic transcriptional-activation function.
Effector kinase transducing the cascade output to MEF2.
Active ERK5 phosphorylates and co-activates MEF2-family transcription factors (MEF2A/C/D), driving proliferation, survival, and endothelial/cardiovascular gene programs.
Converts ERK5 activity into a MEF2-driven gene program.