MAP2K7 (MKK7, JNKK2, MEK7, SKK4) - curation notes
UniProt O14733; human; 419 aa (isoform 1); STE Ser/Thr kinase group, MAP kinase kinase subfamily.
Identity and domain architecture
Molecular function
- Dual-specificity MAP2K; phosphorylates the JNK Thr-Pro-Tyr activation motif, with a strong preference for the Thr
PMID:11390361
[Reactome:R-HSA-168162 "MKK7 a striking preference for the threonine residue (Thr-183)"].
- Thr monophosphorylation by MKK7 is sufficient to raise JNK activity; MKK4 adds the Tyr
PMID:11390361.
- JNK-selective: does not activate p38 or ERK in vitro
PMID:9207092
PMID:9535930.
- Exception: in human neurons, a DLK -> MKK7 -> ERK1/2 route downstream of ApoE; immunoprecipitated MKK7 phosphorylated recombinant ERK2
PMID:28111074. Single study; non-canonical.
- GO: GO:0008545 JUN kinase kinase activity (is_a GO:0004708 MAP kinase kinase activity) is the precise MF, matching the MAP2K4 review.
Activation
- Activated by MAP3K phosphorylation of Ser271/Thr275 (MEKK1, TAK1, ASK1, MLKs, DLK)
[Reactome:R-HSA-450337 "Residues involved in activation of these protein kinases correspond to human Ser271, Thr275 in MKK7"]
PMID:9312068.
- Endogenous MKK7 activated by IL-3, CD40, BCR, Fc receptor, heat, UV, anisomycin, hyperosmolarity and TNF
PMID:9535930.
- TNF and IL-1 activate MKK7 but not MKK4; Mkk7-/- MEFs lose cytokine-induced JNK activation; stress-induced JNK activation needs loss of both MKK4 and MKK7
PMID:11390361
PMID:11390361.
Scaffolds and interactors (for protein-binding rows)
- JIP1/JIP2 scaffolds assemble MLK-MKK7-JNK modules
PMID:10490659.
- TAK1 (MAP3K7) is an upstream MAP3K that phosphorylates MKK7
[Reactome:R-HSA-450321] PMID:17709393.
- Negative regulators that bind MKK7: GADD45beta (blocks catalytic pocket) PMID:25314077, c-FLIPL PMID:17110930, TRIB3 [PMID:15299019, abstract only], RASSF7.
These are functions of the partner (inhibitor), not an informative MF of MKK7; generic protein-binding rows REMOVEd (interaction not disputed).
- DUSP19/SKRP1 binds MKK7 selectively (not MKK4) and scaffolds ASK1-MKK7 (mouse)
PMID:11959862. Basis of the ISS protein phosphatase binding row.
- LRRK2 binds and can phosphorylate MKK3/6/7 PMID:20067578; HSP90AB1 client (kinase-wide screen) PMID:22939624; YWHAE (14-3-3 interactome) PMID:36931259.
Localization
- Cytoplasm and nucleus (UniProt, ISS from mouse); Reactome places the JNK-activating reactions in the cytosol;
anthrax lethal factor cleaves MKK7 in the cytosol [Reactome:R-HSA-5211387].
Physiology
- Mouse Mkk7 knockout is embryonic lethal (Mkk4 too), showing non-redundancy
PMID:11390361.
Annotation judgement calls
- protein kinase activity / protein serine kinase / protein tyrosine kinase IEA -> MODIFY to GO:0004708 (as in MAP2K3/MAP2K4).
- IDA MAP kinase kinase activity (PMID:9535930) ACCEPT; JNKK activity (IBA/ISS/TAS) ACCEPT as core.
- Response-to-stimulus IDA rows (heat, UV, osmotic, TNF) from PMID:9535930: MKK7 activity measured after stimuli; keep as non-core.
- GO:0032206 positive regulation of telomere maintenance (IMP, PMID:21531765): RNAi screen; abstract does not mention MKK7 -> UNDECIDED.
- GO:0019901 protein kinase binding IPI (PMID:14697235): partner DLK/MAP3K12, abstract is a ZPK promoter paper; DLK-MKK7 is a known
activator relationship (UniProt ACTIVITY REGULATION; PMID:28111074 "MKK7, a MAP-kinase kinase that is a major DLK target in neurons")
-> kept as non-core, deferring to curator.
- ERK1/2 cascade and transcription IMP (PMID:28111074): non-canonical neuronal ApoE pathway; ERK kept as non-core, transcription marked over-annotated (indirect, AP-1 driven).
- No PMID:19593445 mechanical-stimulus row exists for MAP2K7.