MAPK7 encodes ERK5 (big MAP kinase 1, BMK1), an 816-residue atypical member of the MAP kinase family. Its N-terminal half is a conventional proline-directed Ser/Thr kinase domain with a TEY activation motif that is dually phosphorylated by the dedicated MAP2K MEK5 (MAP2K5), itself activated by MEKK2/MEKK3; ERK5 does not interact with MEK1/2. A unique ~400-residue C-terminal tail carries a nuclear localization signal, a MEF2-interacting region and a transcriptional activation domain. In resting cells ERK5 is held in the cytoplasm as a client of the HSP90-CDC37 chaperone; activation and C-terminal autophosphorylation release Hsp90 and drive nuclear import, where ERK5 phosphorylates and coactivates MEF2 transcription factors (MEF2A/C/D) and other substrates such as SGK1 and PML. ERK5 is activated by growth factors (EGF), oxidative and osmotic stress and, notably, laminar shear stress in endothelium, where it drives MEF2-dependent KLF2/KLF4 and NRF2 programs that promote endothelial quiescence and survival. Loss of ERK5 in mice causes embryonic lethality from cardiovascular defects, and adult endothelial loss causes vascular leakage and endothelial apoptosis.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000165 MAPK cascade | ISS GO_REF:0000024 | MODIFY | Summary: ERK5 is the terminal kinase of a MAPK cascade (MEKK2/3-MEK5-ERK5); transferred from rat Mapk7. Reason: Correct but generic. GO has a dedicated child term, 'ERK5 cascade' (GO:0070375), defined as a MAPK cascade containing ERK5 (MAPK7/BMK1); rat Mapk7 carries it by IMP. ERK5 performs the terminal phosphorylation step of this cascade, so the specific term is appropriate (as used for MAP2K5). Proposed replacements: ERK5 cascade Supporting Evidence: PMID:9790194 EGF-mediated activation of Bmk1 occurs independently of Ras and requires the MAP-kinase kinase Mek5 file:human/MAPK7/MAPK7-uniprot.txt activator of MAPK7 is the MAPK kinase MAP2K5 PMID:7759517 ERK5 did not interact with MEK1 or MEK2 file:human/MAPK7/MAPK7-deep-research-falcon.md MEK5 is the established direct MAP2K for ERK5. |
| GO:0004672 protein kinase activity | IEA GO_REF:0000120 | MODIFY | Summary: Generic protein kinase activity inferred from the kinase domain. Reason: Correct but too general; ERK5 is a proline-directed Ser/Thr MAP kinase with demonstrated substrates (MEF2C Ser387, SGK1 Ser78). Replace with MAP kinase activity, as in the MAPK1 review. Proposed replacements: MAP kinase activity Supporting Evidence: file:human/MAPK7/MAPK7-uniprot.txt Belongs to the protein kinase superfamily. CMGC Ser/Thr PMID:9384584 BMK1 dramatically enhances the transactivation activity of MEF2C by phosphorylating a serine residue at amino acid position 387 in this transcription factor PMID:11254654 During growth factor-induced cell stimulation, BMK1 activates SGK by phosphorylation at serine 78 |
| GO:0004674 protein serine/threonine kinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of protein serine/threonine kinase activity across the MAPK family node. Reason: ERK5 sits within the MAPK clade (PTHR24055) and phosphorylates Ser/Thr residues of substrates such as MEF2C and SGK1; no evidence of loss of catalytic function. Supporting Evidence: PMID:9384584 BMK1 dramatically enhances the transactivation activity of MEF2C by phosphorylating a serine residue at amino acid position 387 in this transcription factor PMID:11254654 During growth factor-induced cell stimulation, BMK1 activates SGK by phosphorylation at serine 78 |
| GO:0004674 protein serine/threonine kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation of protein serine/threonine kinase activity. Reason: Consistent with experimental substrate phosphorylation data and the IBA. Supporting Evidence: PMID:9384584 BMK1 dramatically enhances the transactivation activity of MEF2C by phosphorylating a serine residue at amino acid position 387 in this transcription factor |
| GO:0004707 MAP kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation of MAP kinase activity. Reason: ERK5 is a TEY-motif MAP kinase activated by dual phosphorylation by MEK5; MAP kinase activity is its core catalytic function. Supporting Evidence: PMID:7646528 Although BMK1 has the dual phosphorylation site of MAP kinases characterized by the TEY sequence found in ERK1 and ERK2 file:human/MAPK7/MAPK7-uniprot.txt activator of MAPK7 is the MAPK kinase MAP2K5 |
| GO:0004707 MAP kinase activity | TAS PMID:7646528 Primary structure of BMK1: a new mammalian map kinase. | ACCEPT | Summary: Cloning paper for BMK1 describing it as a new MAP kinase with the TEY dual-phosphorylation motif. Reason: MAP kinase activity is the core MF of ERK5, supported by later substrate-level evidence (MEF2C, SGK1, PML). Supporting Evidence: PMID:7646528 Although BMK1 has the dual phosphorylation site of MAP kinases characterized by the TEY sequence found in ERK1 and ERK2 PMID:9384584 BMK1 dramatically enhances the transactivation activity of MEF2C by phosphorylating a serine residue at amino acid position 387 in this transcription factor |
| GO:0004857 enzyme inhibitor activity | NAS PMID:16177794 The protein kinase A anchoring protein mAKAP coordinates two... | REMOVE | Summary: In rat cardiomyocyte mAKAP complexes, an ERK5 module suppresses PDE4D3 activity. Reason: The paper shows that ERK phosphorylation of PDE4D3 decreases phosphodiesterase activity, i.e. regulation through catalytic kinase activity with PDE4D3 as substrate, not an enzyme inhibitor molecular function (which implies binding-mediated inhibition). The effect is captured by MAP kinase activity. Supporting Evidence: PMID:16177794 whereas an mAKAP-associated ERK5 kinase module suppresses PDE4D3 PMID:16177794 ERK phosphorylation of PDE4D3 decreases the phosphodiesterase activity |
| GO:0005515 protein binding | IPI PMID:18588859 TGF-beta activates ERK5 in human renal epithelial cells. | MODIFY | Summary: MAPK7/ERK5 interacts with its upstream activating kinase MAP2K5/MEK5 (WITH/FROM UniProtKB:Q13163), reported in PMID:18588859. Reason: MAP2K5/MEK5 is the dedicated upstream MAP kinase kinase that binds ERK5 through its N-terminal region and dual-phosphorylates the TEY motif; ERK5 does not bind MEK1/2. Replace bare protein binding with 'mitogen-activated protein kinase kinase binding', matching the MAPK1 and MAPK14 reviews. Proposed replacements: mitogen-activated protein kinase kinase binding Supporting Evidence: PMID:18588859 TGF-beta increased the association of MEK5 with phospho-ERK5 and MEF2C PMID:7759517 ERK5 did not interact with MEK1 or MEK2 |
| GO:0005515 protein binding | IPI PMID:20832753 Pharmacological inhibition of BMK1 suppresses tumor growth t... | REMOVE | Summary: ERK5/BMK1 co-immunoprecipitates with PML and, once activated, colocalizes with it in PML nuclear bodies; PML is phosphorylated by BMK1. Reason: Bare 'protein binding' is uninformative. PML is best described as an ERK5 substrate (captured as has_input on MAP kinase activity) and a PML-body location annotation already exists; PML is not a kinase, phosphatase or transcription factor, so no informative binding MF fits. Removal does not mean the well-documented ERK5-PML interaction is false. Supporting Evidence: PMID:20832753 We found that BMK1 interacted with promyelocytic leukemia protein (PML), and inhibited its tumor-suppressor function through phosphorylation PMID:20832753 This result indicates that BMK1, upon activation, translocates from the cytosol to the nucleus and, through its kinase domain, colocalizes with PML in PML-NBs |
| GO:0005515 protein binding | IPI PMID:22869143 BMK1 is involved in the regulation of p53 through disrupting... | REMOVE | Summary: Activated BMK1 associates preferentially with PML isoform IV and disrupts the PML-MDM2 interaction. Reason: As for PMID:20832753: bare 'protein binding' to PML is uninformative and no specific binding MF applies. The functional consequence (disruption of PML-MDM2, regulation of p53) is a regulatory effect of the kinase rather than a binding function. Removal does not mean the interaction is false. Supporting Evidence: PMID:22869143 We found that activated big MAP kinase 1 (BMK1) preferentially associates with PML isoform IV and disrupts PML-MDM2 interaction PMID:22869143 IF analysis of p53, PML and activated BMK1 indicated that the three proteins colocalized |
| GO:0005515 protein binding | IPI PMID:23428871 Canonical and kinase activity-independent mechanisms for ext... | MODIFY | Summary: In resting cells ERK5 is held in the cytosol as a client of the HSP90AB1-CDC37 chaperone complex; activation releases Hsp90 and allows nuclear translocation. Reason: The interaction is a well-characterized kinase-client/chaperone relationship that controls ERK5 stability and nucleocytoplasmic distribution. 'Hsp90 protein binding' captures it more informatively than bare protein binding. Proposed replacements: Hsp90 protein binding Supporting Evidence: PMID:23428871 We show that ERK5 interacts with the Hsp90-Cdc37 chaperone in resting cells, and that inhibition of Hsp90 or Cdc37 results in ERK5 ubiquitylation and proteasomal degradation PMID:23428871 We also show that the Cdc37-ERK5-Hsp90 complex resides in the cytosol of resting cells and that ERK5 activation results in Hsp90 dissociation and nuclear translocation of the kinase |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Yeast two-hybrid interaction with a UBE2C isoform entry (Q5TZN3) from a proteome-scale binary interactome map. Reason: Bare 'protein binding' conveys no functional information. The partner has no established functional relationship with ERK5 beyond detection in this screen, so no informative replacement MF can be justified. Removal reflects the uninformative term, not a claim that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of |
| GO:0005515 protein binding | IPI PMID:26871637 Widespread Expansion of Protein Interaction Capabilities by ... | MODIFY | Summary: Binary interaction of ERK5 with a MEF2A splice isoform (Q02078-6), detected in an isoform-resolved interactome screen. Reason: Although detected in a screen, the ERK5-MEF2 interaction is independently established: ERK5 binds the MADS/MEF2 domain of MEF2 proteins, phosphorylates MEF2A/C and coactivates MEF2 via its C-terminal tail. Replace bare protein binding with 'DNA-binding transcription factor binding', as used for transcription-factor partners in the MAPK1 review. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: PMID:26871637 used protein-protein interaction profiling to functionally compare hundreds of protein isoform pairs PMID:9753748 The interacting domain of MEF2 was mapped to the N-terminus which contains the highly conserved MADS and MEF2 domains PMID:11046135 the C-terminal region of ERK5 contains a MEF2-interacting domain and, surprisingly, also a potent transcriptional activation domain |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MODIFY | Summary: MAPK7/ERK5 interacts with its upstream activating kinase MAP2K5/MEK5 (WITH/FROM UniProtKB:Q13163), reported in PMID:28514442. Reason: MAP2K5/MEK5 is the dedicated upstream MAP kinase kinase that binds ERK5 through its N-terminal region and dual-phosphorylates the TEY motif; ERK5 does not bind MEK1/2. Replace bare protein binding with 'mitogen-activated protein kinase kinase binding', matching the MAPK1 and MAPK14 reviews. Proposed replacements: mitogen-activated protein kinase kinase binding Supporting Evidence: PMID:28514442 Understanding the architecture of the human proteome has the potential to inform cellular, structural, and evolutionary mechanisms PMID:7759517 ERK5 did not interact with MEK1 or MEK2 |
| GO:0005515 protein binding | IPI PMID:31980649 Extensive rewiring of the EGFR network in colorectal cancer ... | REMOVE | Summary: Interaction with the co-chaperone BAG2 detected in an AP-MS interaction network study of KRAS-mutant colorectal cancer cells. Reason: Bare 'protein binding' conveys no functional information. The partner has no established functional relationship with ERK5 beyond detection in this screen, so no informative replacement MF can be justified. Removal reflects the uninformative term, not a claim that the interaction is false. Supporting Evidence: PMID:31980649 Here, we analyze how a common oncogenic KRAS mutation (KRASG13D) affects PPIN structure and function of the Epidermal Growth Factor Receptor (EGFR) network in colorectal cancer (CRC) cells. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Binary (yeast two-hybrid) interaction with UBE2C from the HuRI reference interactome. Reason: Bare 'protein binding' conveys no functional information. The partner has no established functional relationship with ERK5 beyond detection in this screen, so no informative replacement MF can be justified. Removal reflects the uninformative term, not a claim that the interaction is false. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Binary (yeast two-hybrid) interaction with ZKSCAN1 from the HuRI reference interactome. Reason: Bare 'protein binding' conveys no functional information. The partner has no established functional relationship with ERK5 beyond detection in this screen, so no informative replacement MF can be justified. Removal reflects the uninformative term, not a claim that the interaction is false. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MODIFY | Summary: MAPK7/ERK5 interacts with its upstream activating kinase MAP2K5/MEK5 (WITH/FROM UniProtKB:Q13163), reported in PMID:32296183. Reason: MAP2K5/MEK5 is the dedicated upstream MAP kinase kinase that binds ERK5 through its N-terminal region and dual-phosphorylates the TEY motif; ERK5 does not bind MEK1/2. Replace bare protein binding with 'mitogen-activated protein kinase kinase binding', matching the MAPK1 and MAPK14 reviews. Proposed replacements: mitogen-activated protein kinase kinase binding Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. PMID:7759517 ERK5 did not interact with MEK1 or MEK2 |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Binary (yeast two-hybrid) interaction with CCDC6 from the HuRI reference interactome. Reason: Bare 'protein binding' conveys no functional information. The partner has no established functional relationship with ERK5 beyond detection in this screen, so no informative replacement MF can be justified. Removal reflects the uninformative term, not a claim that the interaction is false. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32707033 Kinase Interaction Network Expands Functional and Disease Ro... | MODIFY | Summary: MAPK7/ERK5 interacts with its upstream activating kinase MAP2K5/MEK5 (WITH/FROM UniProtKB:Q13163), reported in PMID:32707033. Reason: MAP2K5/MEK5 is the dedicated upstream MAP kinase kinase that binds ERK5 through its N-terminal region and dual-phosphorylates the TEY motif; ERK5 does not bind MEK1/2. Replace bare protein binding with 'mitogen-activated protein kinase kinase binding', matching the MAPK1 and MAPK14 reviews. Proposed replacements: mitogen-activated protein kinase kinase binding Supporting Evidence: PMID:32707033 Here, we present a comprehensive mass-spectrometry-based analysis of a human kinase interaction network covering more than 300 kinases. PMID:7759517 ERK5 did not interact with MEK1 or MEK2 |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MODIFY | Summary: MAPK7/ERK5 interacts with its upstream activating kinase MAP2K5/MEK5 (WITH/FROM UniProtKB:Q13163), reported in PMID:33961781. Reason: MAP2K5/MEK5 is the dedicated upstream MAP kinase kinase that binds ERK5 through its N-terminal region and dual-phosphorylates the TEY motif; ERK5 does not bind MEK1/2. Replace bare protein binding with 'mitogen-activated protein kinase kinase binding', matching the MAPK1 and MAPK14 reviews. Proposed replacements: mitogen-activated protein kinase kinase binding Supporting Evidence: PMID:33961781 Through affinity-purification mass spectrometry, we have created two proteome-scale, cell-line-specific interaction networks. PMID:7759517 ERK5 did not interact with MEK1 or MEK2 |
| GO:0005515 protein binding | IPI PMID:35512704 Systematic discovery of mutation-directed neo-protein-protei... | REMOVE | Summary: Interaction with BRAF detected in a high-throughput screen for mutation-directed neomorphic protein-protein interactions. Reason: Bare 'protein binding' is uninformative. BRAF is not a recognized component or regulator of the MEKK2/3-MEK5-ERK5 module, and a screen hit alone does not justify asserting 'protein kinase binding' as an ERK5 function. Removal does not mean the interaction is false. Supporting Evidence: PMID:35512704 Here, we identify prevalent variant-enabled neomorph-protein-protein interactions (neoPPI) with a quantitative high-throughput differential screening (qHT-dS) platform. |
| GO:0005515 protein binding | IPI PMID:7759517 Components of a new human protein kinase signal transduction... | MODIFY | Summary: MAPK7/ERK5 interacts with its upstream activating kinase MAP2K5/MEK5 (WITH/FROM UniProtKB:Q13163), reported in PMID:7759517. Reason: MAP2K5/MEK5 is the dedicated upstream MAP kinase kinase that binds ERK5 through its N-terminal region and dual-phosphorylates the TEY motif; ERK5 does not bind MEK1/2. Replace bare protein binding with 'mitogen-activated protein kinase kinase binding', matching the MAPK1 and MAPK14 reviews. Proposed replacements: mitogen-activated protein kinase kinase binding Supporting Evidence: PMID:7759517 ERK5 was identified by a specific interaction with the MEK5 mutants S311A/T315A and K195M in the yeast two-hybrid system PMID:7759517 ERK5 did not interact with MEK1 or MEK2 |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: ATP binding inferred from the protein kinase ATP-binding site (InterPro). Reason: ERK5 has a canonical kinase ATP-binding site (UniProt BINDING 61-69, 84) required for catalysis. Supporting Evidence: file:human/MAPK7/MAPK7-uniprot.txt Belongs to the protein kinase superfamily. CMGC Ser/Thr |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of nuclear activity for MAPK family members. Reason: Activated ERK5 translocates to the nucleus where it phosphorylates and coactivates MEF2 factors. Supporting Evidence: PMID:23428871 We also show that the Cdc37-ERK5-Hsp90 complex resides in the cytosol of resting cells and that ERK5 activation results in Hsp90 dissociation and nuclear translocation of the kinase file:human/MAPK7/MAPK7-uniprot.txt translocates to the nucleus and phosphorylates various downstream |
| GO:0005634 nucleus | IDA PMID:18588859 TGF-beta activates ERK5 in human renal epithelial cells. | ACCEPT | Summary: Nuclear localization of ERK5 in TGF-beta-stimulated human renal proximal tubule epithelial cells. Reason: Abstract-only cache; nuclear localization of activated ERK5 is well established and the curator read the full text. Supporting Evidence: PMID:18588859 This study demonstrates, fort the first time, ERK5 activation by TGF-beta, observed in both transformed and primary adult human PTEC; activation required ALK-5 receptor activity PMID:18588859 TGF-beta increased the association of MEK5 with phospho-ERK5 and MEF2C |
| GO:0005634 nucleus | IDA PMID:22869143 BMK1 is involved in the regulation of p53 through disrupting... | ACCEPT | Summary: Activated BMK1 translocates from cytoplasm to nucleus and colocalizes with PML/p53. Reason: Directly shown by immunofluorescence. Supporting Evidence: PMID:22869143 BMK1 activation was shown to correspond to its translocation from the cytoplasm to the nucleus PMID:22869143 IF analysis of p53, PML and activated BMK1 indicated that the three proteins colocalized |
| GO:0005634 nucleus | IDA PMID:23043106 Laminar flow activation of ERK5 protein in vascular endothel... | ACCEPT | Summary: Nuclear ERK5 in laminar-flow stimulated endothelial cells. Reason: Abstract-only cache; consistent with the established activation-dependent nuclear translocation of ERK5. Supporting Evidence: PMID:23043106 Laminar flow induces Nrf2 activation dependent on ERK5 activation, leading to up-regulation of downstream genes of Nrf2. |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic nuclear annotation. Reason: Consistent with experimental data. Supporting Evidence: file:human/MAPK7/MAPK7-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Nucleus, PML body. |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: Human Protein Atlas immunofluorescence localization to nucleoplasm. Reason: Consistent with the nuclear pool of ERK5. Supporting Evidence: file:human/MAPK7/MAPK7-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Nucleus, PML body. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-198714 | ACCEPT | Summary: Reactome: phosphorylated ERK5 translocates to the nucleus. Reason: Consistent with activation-dependent nuclear translocation. Supporting Evidence: Reactome:R-HSA-198714 On phosphorylation, ERK5 translocates to the nucleus PMID:23428871 We also show that the Cdc37-ERK5-Hsp90 complex resides in the cytosol of resting cells and that ERK5 activation results in Hsp90 dissociation and nuclear translocation of the kinase |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-198746 | ACCEPT | Summary: Reactome: ERK1/2/5 activate RSK kinases in cytoplasm and nucleus. Reason: Nucleoplasmic location of ERK5 is well supported, independent of the specific RSK reaction. Supporting Evidence: Reactome:R-HSA-198746 RSKs can be activated by the ERKs (ERK1, 2, 5) in the cytoplasm as well as in the nucleus |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-199959 | ACCEPT | Summary: Reactome: ERKs are inactivated by PP2A. Reason: Location is supported; the reaction is modelled generically for ERKs. Supporting Evidence: Reactome:R-HSA-199959 ERKs are inactivated by the protein phosphatase 2A (PP2A) |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-203797 | ACCEPT | Summary: Reactome: ERKs are inactivated by DUSPs. Reason: Location is supported; the reaction is modelled generically for ERKs. Supporting Evidence: Reactome:R-HSA-203797 Over 10 dual specificity phosphatases (DUSPs) active on MAP kinases are known |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of cytoplasmic activity. Reason: Inactive ERK5 resides in the cytoplasm in complex with Hsp90-Cdc37 and is activated there by MEK5. Supporting Evidence: PMID:23428871 We also show that the Cdc37-ERK5-Hsp90 complex resides in the cytosol of resting cells and that ERK5 activation results in Hsp90 dissociation and nuclear translocation of the kinase |
| GO:0005737 cytoplasm | IDA PMID:22869143 BMK1 is involved in the regulation of p53 through disrupting... | ACCEPT | Summary: Non-activated BMK1 is cytoplasmic. Reason: Directly shown by immunofluorescence. Supporting Evidence: PMID:22869143 BMK1 activation was shown to correspond to its translocation from the cytoplasm to the nucleus |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular location mapping to cytoplasm. Reason: Consistent with experimental data. Supporting Evidence: file:human/MAPK7/MAPK7-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Nucleus, PML body. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Human Protein Atlas immunofluorescence localization to cytosol. Reason: Consistent with the resting cytosolic ERK5-Cdc37-Hsp90 complex. Supporting Evidence: PMID:23428871 We also show that the Cdc37-ERK5-Hsp90 complex resides in the cytosol of resting cells and that ERK5 activation results in Hsp90 dissociation and nuclear translocation of the kinase |
| GO:0005829 cytosol | IDA PMID:23043106 Laminar flow activation of ERK5 protein in vascular endothel... | ACCEPT | Summary: Cytosolic ERK5 in endothelial cells. Reason: Abstract-only cache; cytosolic localization of resting ERK5 is well established. Supporting Evidence: PMID:23043106 Molecular interaction between ERK5 and Nrf2 was further induced by laminar flow. PMID:23428871 We also show that the Cdc37-ERK5-Hsp90 complex resides in the cytosol of resting cells and that ERK5 activation results in Hsp90 dissociation and nuclear translocation of the kinase |
| GO:0005829 cytosol | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer of cytosol from mouse Mapk7. Reason: Consistent with human data. Supporting Evidence: PMID:23428871 We also show that the Cdc37-ERK5-Hsp90 complex resides in the cytosol of resting cells and that ERK5 activation results in Hsp90 dissociation and nuclear translocation of the kinase |
| GO:0005829 cytosol | TAS Reactome:R-HSA-198714 | ACCEPT | Summary: Reactome: ERK5 starts in the cytosol before nuclear translocation. Reason: Consistent with experimental data. Supporting Evidence: Reactome:R-HSA-198714 On phosphorylation, ERK5 translocates to the nucleus PMID:23428871 We also show that the Cdc37-ERK5-Hsp90 complex resides in the cytosol of resting cells and that ERK5 activation results in Hsp90 dissociation and nuclear translocation of the kinase |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8855915 | ACCEPT | Summary: Reactome places MAPK7 among cytosolic RET interactors. Reason: The cytosolic location is correct regardless of the tentative RET interaction. Supporting Evidence: Reactome:R-HSA-8855915 Other RET interactors that may have a role in RET signaling include Mitogen-activated protein kinase 7 (MAPK7, BMK1) PMID:23428871 We also show that the Cdc37-ERK5-Hsp90 complex resides in the cytosol of resting cells and that ERK5 activation results in Hsp90 dissociation and nuclear translocation of the kinase |
| GO:0007165 signal transduction | TAS PMID:7646528 Primary structure of BMK1: a new mammalian map kinase. | MODIFY | Summary: Generic signal transduction from the BMK1 cloning paper. Reason: Correct but uninformative; ERK5 is the terminal kinase of the ERK5 cascade (GO:0070375). Matches the MAP2K5 review, where the equivalent generic annotation was refined to ERK5 cascade. Proposed replacements: ERK5 cascade Supporting Evidence: PMID:7646528 Although BMK1 has the dual phosphorylation site of MAP kinases characterized by the TEY sequence found in ERK1 and ERK2 PMID:9790194 EGF-mediated activation of Bmk1 occurs independently of Ras and requires the MAP-kinase kinase Mek5 |
| GO:0007189 adenylate cyclase-activating G protein-coupled receptor signaling pathway | NAS PMID:16177794 The protein kinase A anchoring protein mAKAP coordinates two... | REMOVE | Summary: cAMP, via Epac1/Rap1 in the mAKAP complex, attenuates ERK5 activity in rat cardiomyocytes. Reason: ERK5 is a target of cAMP cross-talk (it is suppressed by cAMP) rather than a component that executes adenylate cyclase-activating GPCR signalling; the experiments used forskolin/cAMP analogues rather than receptor stimulation. Non-experimental (NAS) annotation of an indirect relationship. Supporting Evidence: PMID:16177794 PDE4D3 also functions as an adaptor protein that recruits Epac1, an exchange factor for the small GTPase Rap1, to enable cAMP-dependent attenuation of ERK5 |
| GO:0016605 PML body | IDA PMID:22869143 BMK1 is involved in the regulation of p53 through disrupting... | KEEP AS NON CORE | Summary: Activated BMK1 colocalizes with PML and p53 in PML nuclear bodies. Reason: Directly observed, but PML body localization is a specific context of the nuclear pool rather than the principal site of ERK5 action. Supporting Evidence: PMID:22869143 IF analysis of p53, PML and activated BMK1 indicated that the three proteins colocalized PMID:20832753 This result indicates that BMK1, upon activation, translocates from the cytosol to the nucleus and, through its kinase domain, colocalizes with PML in PML-NBs |
| GO:0016605 PML body | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt subcellular location mapping to PML body. Reason: Derived from the PML-body colocalization studies; valid but non-core. Supporting Evidence: file:human/MAPK7/MAPK7-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Nucleus, PML body. |
| GO:0033554 cellular response to stress | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA prediction of cellular response to stress. Reason: ERK5 is activated by oxidative and osmotic stress and shear stress, but this broad term adds little beyond more specific annotations. Supporting Evidence: file:human/MAPK7/MAPK7-uniprot.txt Activated in response to PMID:23043106 Further functional studies showed that ERK5 provides protection against oxidative stress-induced cytotoxicity dependent on Nrf2. |
| GO:0034115 negative regulation of heterotypic cell-cell adhesion | IGI PMID:20551324 Erk5 activation elicits a vasoprotective endothelial phenoty... | KEEP AS NON CORE | Summary: Constitutive MEK5D/Erk5 activation in HUVEC reduced inflammatory properties, including leukocyte-endothelial adhesion, dependent on KLF4. Reason: Abstract-only cache; downstream endothelial phenotype mediated by transcriptional induction of KLF4. Retain as a non-core consequence. Supporting Evidence: PMID:20551324 We provide evidence that constitutive Erk5 activation elicits an overall protective phenotype characterized by increased apoptosis resistance and a decreased angiogenic, migratory, and inflammatory potential PMID:20551324 We identify KLF4 as a novel Erk5 target and demonstrate a critical role of this transcription factor downstream of Erk5 |
| GO:0034392 negative regulation of smooth muscle cell apoptotic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transferred from rat Mapk7: ERK5 protects smooth muscle cells from apoptosis. Reason: ERK5 has anti-apoptotic roles in several cell types (endothelium, cardiomyocytes); smooth-muscle survival is a non-core, cell-type-specific outcome. Supporting Evidence: file:human/MAPK7/MAPK7-uniprot.txt acts as a negative regulator of apoptosis in cardiomyocytes |
| GO:0035556 intracellular signal transduction | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of intracellular signal transduction for the MAPK family. Reason: ERK5 relays MEK5 signals to cytoplasmic and nuclear targets; consistent with MAPK1/MAPK14 reviews. Supporting Evidence: PMID:9790194 These results demonstrate that Bmk1 is part of a distinct MAP-kinase signalling pathway that is required for EGF-induced cell proliferation and progression through the cell cycle file:human/MAPK7/MAPK7-uniprot.txt translocates to the nucleus and phosphorylates various downstream |
| GO:0043066 negative regulation of apoptotic process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA prediction of negative regulation of apoptotic process. Reason: ERK5 promotes survival of endothelial cells and cardiomyocytes, but as a downstream consequence of its kinase and coactivator activities. Supporting Evidence: PMID:15085193 In vitro removal of BMK1 protein also led to the death of endothelial cells partially due to the deregulation of transcriptional factor MEF2C, which is a direct substrate of BMK1 file:human/MAPK7/MAPK7-uniprot.txt acts as a negative regulator of apoptosis in cardiomyocytes |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IGI PMID:20551324 Erk5 activation elicits a vasoprotective endothelial phenoty... | ACCEPT | Summary: Erk5 activation induces KLF4 and KLF4-dependent gene expression in endothelial cells. Reason: ERK5 positively regulates Pol II transcription both by phosphorylating MEF2 factors and through its own C-terminal transactivation domain, which coactivates MEF2 at target promoters; this is a core function. Supporting Evidence: PMID:20551324 We identify KLF4 as a novel Erk5 target and demonstrate a critical role of this transcription factor downstream of Erk5 PMID:20551324 we show that vasoprotective statins potently induce KLF4 and KLF4-dependent gene expression via activation of Erk5 PMID:11046135 These domains are both required for coactivation of MEF2D by ERK5 |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IMP PMID:23043106 Laminar flow activation of ERK5 protein in vascular endothel... | ACCEPT | Summary: ERK5 knockdown/inhibition blocks laminar-flow induced Nrf2-dependent gene expression. Reason: Abstract-only cache but the abstract states the finding directly; positive regulation of transcription is a core ERK5 output. Supporting Evidence: PMID:23043106 Laminar flow induces Nrf2 activation dependent on ERK5 activation, leading to up-regulation of downstream genes of Nrf2. |
| GO:0050728 negative regulation of inflammatory response | TAS PMID:20551324 Erk5 activation elicits a vasoprotective endothelial phenoty... | KEEP AS NON CORE | Summary: Erk5 activation decreases the inflammatory potential of endothelial cells. Reason: Downstream physiological outcome of the ERK5-KLF4 program; valid but not core. Supporting Evidence: PMID:20551324 We provide evidence that constitutive Erk5 activation elicits an overall protective phenotype characterized by increased apoptosis resistance and a decreased angiogenic, migratory, and inflammatory potential |
| GO:0051019 mitogen-activated protein kinase binding | IPI PMID:23043106 Laminar flow activation of ERK5 protein in vascular endothel... | MODIFY | Summary: ERK5 interacts with Nrf2 (WITH/FROM UniProtKB:Q16236, NFE2L2) under laminar flow. Reason: The WITH partner NFE2L2/Nrf2 is a bZIP transcription factor, not a mitogen-activated protein kinase, so 'mitogen-activated protein kinase binding' does not describe what MAPK7 binds here. The interaction itself is reported in the abstract; 'DNA-binding transcription factor binding' is the accurate MF. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: PMID:23043106 Molecular interaction between ERK5 and Nrf2 was further induced by laminar flow. |
| GO:0051247 positive regulation of protein metabolic process | IGI PMID:20551324 Erk5 activation elicits a vasoprotective endothelial phenoty... | MARK AS OVER ANNOTATED | Summary: Erk5 activation increases KLF4 (and KLF4 target) protein levels in endothelial cells. Reason: The term 'positive regulation of protein metabolic process' is very broad and describes an indirect consequence of transcriptional induction; it adds no information beyond the transcription-regulation annotation. Supporting Evidence: PMID:20551324 We identify KLF4 as a novel Erk5 target and demonstrate a critical role of this transcription factor downstream of Erk5 |
| GO:0060761 negative regulation of response to cytokine stimulus | IGI PMID:20551324 Erk5 activation elicits a vasoprotective endothelial phenoty... | KEEP AS NON CORE | Summary: Erk5/KLF4 activation dampens endothelial responses to inflammatory cytokines. Reason: Abstract-only cache; plausible downstream outcome of the ERK5-KLF4 program. Supporting Evidence: PMID:20551324 We provide evidence that constitutive Erk5 activation elicits an overall protective phenotype characterized by increased apoptosis resistance and a decreased angiogenic, migratory, and inflammatory potential |
| GO:0070301 cellular response to hydrogen peroxide | IMP PMID:23043106 Laminar flow activation of ERK5 protein in vascular endothel... | KEEP AS NON CORE | Summary: ERK5 mediates Nrf2-dependent protection of endothelial cells from oxidative stress. Reason: ERK5 is activated by H2O2 and mediates protective responses; valid response term but not core function. Supporting Evidence: PMID:23043106 Further functional studies showed that ERK5 provides protection against oxidative stress-induced cytotoxicity dependent on Nrf2. file:human/MAPK7/MAPK7-uniprot.txt Activated in response to |
| GO:0071363 cellular response to growth factor stimulus | IGI PMID:20551324 Erk5 activation elicits a vasoprotective endothelial phenoty... | KEEP AS NON CORE | Summary: Cellular response to growth factor stimulus in endothelial cells. Reason: ERK5 is activated by growth factors such as EGF and mediates proliferative responses; response term is valid but non-core. Supporting Evidence: PMID:9790194 EGF-mediated activation of Bmk1 occurs independently of Ras and requires the MAP-kinase kinase Mek5 PMID:20551324 we show that vasoprotective statins potently induce KLF4 and KLF4-dependent gene expression via activation of Erk5 |
| GO:0071499 cellular response to laminar fluid shear stress | IMP PMID:23043106 Laminar flow activation of ERK5 protein in vascular endothel... | ACCEPT | Summary: ERK5 is required for laminar-flow induced Nrf2 activation and gene expression in HUVEC. Reason: Laminar shear stress is the best-established physiological activator of endothelial ERK5, and ERK5 transduces it into atheroprotective transcriptional programs; accepted as core physiological context (consistent with MAP2K5 review). Supporting Evidence: PMID:23043106 Laminar flow induces Nrf2 activation dependent on ERK5 activation, leading to up-regulation of downstream genes of Nrf2. PMID:23043106 laminar flow-induced activation of ERK5-Nrf2 signal pathway plays a critical role for anti-inflammatory and anti-apoptotic mechanism in endothelial cells |
| GO:0071499 cellular response to laminar fluid shear stress | TAS PMID:20551324 Erk5 activation elicits a vasoprotective endothelial phenoty... | ACCEPT | Summary: MEK5/Erk5 as the candidate pathway mediating beneficial effects of laminar flow. Reason: See IMP annotation; flow-induced ERK5 signalling is well established. Supporting Evidence: PMID:20551324 The MEK5/Erk5 MAPK cascade has recently been implicated in the regulation of endothelial integrity and represents a candidate pathway mediating the beneficial effects of laminar flow |
| GO:0071560 cellular response to transforming growth factor beta stimulus | IDA PMID:18588859 TGF-beta activates ERK5 in human renal epithelial cells. | KEEP AS NON CORE | Summary: TGF-beta activates ERK5 in human proximal tubule epithelial cells via ALK5. Reason: Directly observed activation; one of many context-specific stimuli of ERK5. Supporting Evidence: PMID:18588859 This study demonstrates, fort the first time, ERK5 activation by TGF-beta, observed in both transformed and primary adult human PTEC; activation required ALK-5 receptor activity |
| GO:0106310 protein serine kinase activity | IEA GO_REF:0000116 | ACCEPT | Summary: Rhea-based mapping of protein serine kinase activity. Reason: Correct (e.g. MEF2C Ser387, SGK1 Ser78), though subsumed by MAP kinase activity. Supporting Evidence: PMID:9384584 BMK1 dramatically enhances the transactivation activity of MEF2C by phosphorylating a serine residue at amino acid position 387 in this transcription factor PMID:11254654 During growth factor-induced cell stimulation, BMK1 activates SGK by phosphorylation at serine 78 |
| GO:1902176 negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway | IMP PMID:23043106 Laminar flow activation of ERK5 protein in vascular endothel... | KEEP AS NON CORE | Summary: ERK5 protects endothelial cells against oxidative stress-induced cytotoxicity dependent on Nrf2. Reason: Abstract-only cache; downstream anti-apoptotic outcome. Supporting Evidence: PMID:23043106 Further functional studies showed that ERK5 provides protection against oxidative stress-induced cytotoxicity dependent on Nrf2. |
| GO:2000352 negative regulation of endothelial cell apoptotic process | IMP PMID:23043106 Laminar flow activation of ERK5 protein in vascular endothel... | ACCEPT | Summary: ERK5 suppresses endothelial cell apoptosis. Reason: Endothelial survival is the clearest in vivo role of ERK5: adult deletion causes endothelial apoptosis and vascular leakage, and endothelial-specific deletion phenocopies global loss. Supporting Evidence: PMID:23043106 laminar flow-induced activation of ERK5-Nrf2 signal pathway plays a critical role for anti-inflammatory and anti-apoptotic mechanism in endothelial cells PMID:15085193 In vitro removal of BMK1 protein also led to the death of endothelial cells partially due to the deregulation of transcriptional factor MEF2C, which is a direct substrate of BMK1 PMID:15085193 the data provide direct genetic evidence that the BMK1 pathway is critical for endothelial function and for maintaining blood vessel integrity |
| GO:2001240 negative regulation of extrinsic apoptotic signaling pathway in absence of ligand | IGI PMID:20551324 Erk5 activation elicits a vasoprotective endothelial phenoty... | KEEP AS NON CORE | Summary: Constitutive Erk5 activation increases apoptosis resistance of endothelial cells. Reason: Abstract-only cache; the specific extrinsic-pathway branch cannot be verified, retained as non-core. Supporting Evidence: PMID:20551324 We provide evidence that constitutive Erk5 activation elicits an overall protective phenotype characterized by increased apoptosis resistance and a decreased angiogenic, migratory, and inflammatory potential |
| GO:0003713 transcription coactivator activity | IDA PMID:11046135 ERK5 is a novel type of mitogen-activated protein kinase con... | NEW | Summary: The ERK5 C-terminal tail contains a MEF2-interacting domain and a potent transcriptional activation domain that coactivates MEF2D. Reason: ERK5 itself supplies the activation domain that stimulates MEF2-dependent transcription (it does the work, not merely a kinase acting on a substrate), and this TAD activity persists in kinase-inactive ERK5 and is paradoxically activated by ATP-site inhibitors. No existing MF annotation captures this kinase-independent coactivator function. Supporting Evidence: PMID:11046135 the C-terminal region of ERK5 contains a MEF2-interacting domain and, surprisingly, also a potent transcriptional activation domain PMID:11046135 These domains are both required for coactivation of MEF2D by ERK5 PMID:32170057 The dual protein kinase-transcription factor, ERK5, is an emerging drug target in cancer and inflammation PMID:32170057 ERK5 kinase inhibitors cause paradoxical activation of ERK5 transcriptional activity mediated through its unique C-terminal transcriptional activation domain (TAD) file:human/MAPK7/MAPK7-deep-research-falcon.md Consequently, gene regulation can involve both phosphorylation of other transcription factors and kinase-independent or partly kinase-independent action of ERK5’s own tail. |
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Download this section (compressed HTML)Q: Should the kinase-independent transcriptional activation by the ERK5 C-terminal tail be captured as transcription coactivator activity (GO:0003713) on MAPK7, and would a GO-CAM model need two separate ERK5 activities (MAP kinase activity and coactivator activity) feeding MEF2?
Q: Which physiological ERK5 functions (e.g. endothelial survival, vascular integrity) depend on catalytic activity versus the C-terminal TAD, given that selective kinase inhibitors fail to phenocopy genetic loss?
Q: Is the reported ERK5-Nrf2 (NFE2L2) interaction direct, and is Nrf2 an ERK5 substrate, or does ERK5 act on Nrf2 indirectly (e.g. via KLF2 or KEAP1)?
Experiment: Endothelial-specific knock-in of kinase-dead versus TAD-deleted Mapk7 alleles in mice to separate catalytic and transcriptional functions in vascular integrity.
Experiment: Quantitative phosphoproteomics in human endothelial cells after acute analog-sensitive ERK5 inhibition to define direct substrates under laminar flow.
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