MAP2K3 (MKK3) curation notes

UniProt P46734 (MP2K3_HUMAN), 347 aa, HGNC:6843. STE-group protein kinase, MAP kinase kinase subfamily.

Identity and catalytic function

• Dual-specificity MAP2K: [file:human/MAP2K3/MAP2K3-uniprot.txt "Dual specificity kinase. Is activated by cytokines and"; "of a threonine and a tyrosine residue in the MAP kinase p38."]
• Cloned alongside MKK4 as a p38 activator that does not activate ERK: PMID:7839144 -> unlike MKK4, MKK3 is p38-selective (does not activate JNK).
• Activated MKK3 selectively increases p38 activity in cells; downstream reporter output via ATF2/Elk-1: PMID:8622669
• Activation loop: Ser218/Thr222 (canonical isoform numbering) are the MAP3K target sites; S/T->A inactivates, S/T->E constitutively activates [file:human/MAP2K3/MAP2K3-uniprot.txt "Activated by dual phosphorylation on Ser-218 and"]. Reactome describes the same sites as Ser189/Thr193 (isoform 1 numbering, which lacks residues 1-29) [Reactome:R-HSA-450346 "Residues involved into these protein kinases activation correspond to human sites Ser189 and Thr193 for MKK3"].
• p38 selectivity: [Reactome:R-HSA-450346 "both phosphorylate and activate p38 MAP kinase at its activation site Thr-Gly-Tyr but do not phosphorylate or activate Erk1/2 or SAPK/JNK."] Note that this Reactome summary contains a typo ("MKK3 (MAP2K4)").
• Deep research (falcon) summary: [file:human/MAP2K3/MAP2K3-deep-research-falcon.md "The strongest conclusion is that MKK3 is selective at the MAPK-family level for p38 MAPKs, rather than ERK1/2 or JNK."] Within the p38 family, p38alpha (Thr180/Tyr182) best established; isoform preferences vs MKK6 are context dependent.
• UniProt Rhea mappings list Ser, Thr and Tyr protein kinase reactions for EC 2.7.12.2 (all attributed to PMID:8622669). The physiologically established reaction is Thr+Tyr phosphorylation of the p38 TGY motif; the serine reaction is a generic EC-level mapping. Treat GO:0106310 / GO:0004713 / GO:0004672 as less informative than GO:0004708 (same handling as MAP2K2 review).

Upstream activators (MAP3Ks)

• ASK1/MAP3K5: [Reactome:R-HSA-3228469 "MAP3K5 (ASK1) phosphorylates and activates MAP2K3 (MKK3) and MAP2K6 (MKK6)"]; ASK1 "substrate MKK3" complex PMID:21771788.
• TAK1 (Reactome R-HSA-450346, R-HSA-450302).
• TAO2/TAOK2: PMID:11279118
• LRRK2 binds and phosphorylates MKK3: PMID:20067578
• Deep research lists MEKK1-4, MLK2/3, DLK, ASK1, Tpl2/Cot, TAK1 as upstream MAP3Ks.

Downstream / other partners

• p38alpha (MAPK14) is the substrate; interaction seen in multiple HT interactome studies (PMID:23602568, 31980649, 32707033, 33961781) and UniProt IntAct (NbExp=7). Mxi2 (p38alpha splice variant) binds MKK3/6 PMID:17255949.
• DYRK1B/Mirk: co-IP and MKK3 enhanced Mirk kinase activity PMID:11980910. Whether MKK3 phosphorylates Mirk directly is not stated in the abstract.
• AKAP13-PKN1 signalosome with MAPK14, ZAK (MAP3K20) and MAP2K3 downstream of ADRA1B (UniProt, PMID:21224381).
• TINF2: only from a genome-wide BiFC screen (PMID:21044950); no functional follow-up.

Localisation

• Cytoplasm and nucleus: [Reactome:R-HSA-450296 "The p38 activators MKK3 (MAP2K3) and MKK6 (MAP2K6) were present in both the nucleus and the cytoplasm"]. Membrane detection in NK-cell membrane proteome (PMID:19946888) is HT; ARRB1-dependent recruitment to plasma membrane signalosome reported (UniProt PMID:16709866).

Biological context (downstream, non-core)

• VEGF-induced endothelial migration: PMID:22696064
• Hippo/YAP: MKK3 overexpression promotes F-actin accumulation and YAP nuclear localisation PMID:27402810 - indirect, via p38/actin.
• Osmotic stress (sorbitol activates TAO2 toward MEK3/6, PMID:11279118), LPS/inflammation, ischemia, senescence (Reactome oxidative-stress-induced senescence): p38 pathway contexts.
• Anthrax lethal factor cleaves MKK3 in cytosol (Reactome R-HSA-5211400); Yersinia YopJ acetylates MKK3 activation-loop residues (UniProt).

Curation decisions summary

• Core MF: GO:0004708 MAP kinase kinase activity (IDA, IBA, TAS, IEA all accepted).
• Core BP: GO:0038066 p38MAPK cascade (IMP/IEA/TAS accepted); GO:0031098 SAPK cascade accepted (parent).
• Kinase residue-type terms (GO:0004672, GO:0004713, GO:0106310) -> MODIFY to GO:0004708, following MAP2K2 review.
• Protein binding (12 rows): MAPK14 partners -> GO:0051019 MAP kinase binding; MAP3K5 -> GO:0031435 MAPKKK binding; LRRK2 and DYRK1B -> GO:0019901 protein kinase binding; TINF2 (HT BiFC only) -> REMOVE.
• TAOK2 protein kinase binding IPI -> MODIFY to GO:0031435 (TAO2 acts as a MAP3K for MEK3/6).
• Downstream contexts (VEGF response, EC migration, Hippo, senescence, LPS, sorbitol, ischemia) -> KEEP_AS_NON_CORE; heart development (rat IEA) and positive regulation of transcription (Mirk/HNF1a reporter, indirect) -> MARK_AS_OVER_ANNOTATED.