MAPK7 (ERK5 / BMK1) curation notes

UniProt Q13164, human, 816 aa. CMGC Ser/Thr kinase, MAP kinase subfamily (PANTHER PTHR24055).

Identity and architecture

Cloned independently as BMK1 and ERK5 in 1995. BMK1 "has the dual phosphorylation site of MAP
kinases characterized by the TEY sequence found in ERK1 and ERK2, it has a distinct C-terminal and
loop-12 structure" PMID:7646528.
ERK5 was found as a specific two-hybrid partner of MEK5 and does not bind MEK1/2
PMID:7759517.
UniProt features: kinase domain 55-347, TXY motif 219-221, MAP2K5-binding region 78-139,
NLS 505-539, long disordered C-terminal tail (406-806). UniProt SUBUNIT: interacts with MAP2K5,
MEF2A/C/D, SGK1, PML, HSP90AB1-CDC37, STUB1 [file:human/MAPK7/MAPK7-uniprot.txt].

MAP kinase activity: MEK5 is the dedicated MAP2K; activated ERK5 phosphorylates MEF2C Ser387
PMID:9384584,
SGK1 Ser78 PMID:11254654, and PML
PMID:20832753.
Transcriptional coactivator: the C-terminal tail contains a MEF2-interacting domain and a potent
transcriptional activation domain required for MEF2D coactivation
PMID:11046135.
Lochhead 2020 describes ERK5 as a "dual protein kinase-transcription factor"; kinase inhibitors
paradoxically activate the TAD PMID:32170057.
-> Candidate NEW MF: GO:0003713 transcription coactivator activity. Participation test: ERK5 itself
supplies the activation domain (it does the work), and binds MEF2 directly (MADS/MEF2 domain;
PMID:9753748). Comparator: other coactivators binding MEF2 (e.g. EP300, NCOA2) carry
GO:0003713; kinases are not annotated with it by default, but ERK5 is unusual in having a TAD.
MEF2 binding: direct binding to MEF2 MADS/MEF2 domain PMID:9753748.
-> DNA-binding transcription factor binding (GO:0140297) as replacement for bare protein binding with MEF2A.

Cytoplasmic in resting cells bound to HSP90-CDC37; activation causes Hsp90 dissociation and nuclear
translocation PMID:23428871.
Activated BMK1 colocalizes with PML in PML nuclear bodies PMID:20832753.

ERK5 cascade (GO:0070375): MEKK2/3 -> MEK5 -> ERK5. EGF activates Bmk1 Ras-independently via MEK5
PMID:9790194.
GOA human MAPK7 lacks GO:0070375 (rat Mapk7 has it by IMP, PMID:11782488); the ISS "MAPK cascade"
annotation transferred from rat P0C865 should be refined to ERK5 cascade.
Endothelial integrity/survival: global Erk5 KO lethal E9.5-10.5 with vascular and cardiac defects
PMID:12093914;
adult deletion causes leaky vessels and endothelial apoptosis, endothelial-specific KO phenocopies
global KO PMID:15085193.
Shear stress: laminar flow activates ERK5 -> Nrf2 PMID:23043106; MEK5D-driven Erk5 activation
induces KLF4 and a vasoprotective (anti-apoptotic, anti-inflammatory) endothelial phenotype
PMID:20551324.
Cardiomyocyte survival via STUB1/CHIP-mediated ICER degradation PMID:20724525 (mouse/rat).
PML/p53: activated BMK1 disrupts PML-MDM2 interaction PMID:22869143.
TGF-beta activates ERK5 in renal PTEC (ALK5 dependent) PMID:18588859.
mAKAP complex (rat cardiomyocytes): ERK5 recruited via PDE4D3, phosphorylates and suppresses PDE4D3;
cAMP/Epac1/Rap1 attenuates ERK5 PMID:16177794. Note: this is kinase-mediated inhibition, not
"enzyme inhibitor activity"; ERK5 is regulated by cAMP but is not a component of Gs-coupled GPCR
signalling.

GO:0051019 MAPK binding (IPI, PMID:23043106) has WITH = NFE2L2 (Q16236), which is not a MAPK. The
interaction ERK5-Nrf2 is real (abstract: "Molecular interaction between ERK5 and Nrf2 was further
induced by laminar flow"), so MODIFY to DNA-binding transcription factor binding rather than REMOVE.
Protein binding: MAP2K5 partners -> MAPKK binding (GO:0031434) as in MAPK14/MAPK1; HSP90AB1/CDC37 ->
Hsp90 protein binding (GO:0051879); MEF2A -> GO:0140297; PML (a substrate) and HT-only partners
(BAG2, UBE2C, ZKSCAN1, CCDC6, BRAF) -> REMOVE (uninformative; the interaction is not claimed false).
Enzyme inhibitor activity (NAS) -> REMOVE; AC-activating GPCR signalling (NAS) -> REMOVE.