MAP3K1 (MEKK1) curation notes

UniProt Q13233; 1512 aa; STE Ser/Thr kinase family, MAP3K subfamily. Kinase domain 1243-1508
(active site D1369); SWIM zinc finger 338-366; RING/PHD zinc finger 443-492; TOG domain ~542-888;
caspase-3 site at Asp878 separating the N-terminal regulatory half from the C-terminal kinase.

Kinase function (core)

• Phosphorylates MKK4/SEK1/JNKK1 to activate SAPK/JNK:
  PMID:7997270
• MKK4 is the preferred substrate in vitro, with a stable direct MEKK1:MKK4 complex:
  PMID:9808624
  PMID:9808624
• MKK7 is a weaker substrate; MKK3/MKK6 (p38 arm) also activated:
  PMID:9639556
  PMID:9639556
• ERK arm (MKK1) is context dependent; low-level expression favours JNK:
  PMID:9808624
  PMID:12456688
• IKK activation (NF-kB) — Reactome R-HSA-933530: "MEKK1 phosphorylates Ser-176 and Ser-180 in IKKA and Ser-177 and Ser-181 in IKKB activation loop"
  (TAS; the underlying primary papers are not cached here). IKKs are not MAP2Ks, so this output is not strictly
  "MAP kinase kinase kinase activity", but the term remains correct for the gene.
• Activation mechanism: oligomerisation-induced autophosphorylation, promoted by GCK (MAP4K2) and TRAF2:
  PMID:11784851
  PMID:11784851
• Negative regulation by STK38 via direct interaction with the catalytic domain:
  PMID:17906693
• Kinase-dead MEKK1 blocks TNF- and EGF-induced JNK activation (receptor-coupled signalling):
  PMID:9808624

E3 ubiquitin ligase function (core, unusual among MAP3Ks)

• PHD/RING domain ubiquitinates ERK2 PMID:12049732
• c-Jun ubiquitination/degradation under osmotic stress PMID:17101801
• Self-ubiquitylation inhibits kinase output PMID:12456688
• K63 chains on TAB1 with UBE2N (mouse ES cells, abstract only) PMID:25260751

TOG domain / tubulin binding

• PMID:32817551
• ITC: 1:1 binding to free tubulin, KD 0.63 uM; no binding to taxol-stabilised microtubules
  PMID:32817551.
  Not currently in GOA -> proposed as NEW GO:0015631 tubulin binding.

Localization

• Cytosolic signalling protein (IBA, Reactome TAS). Partial recruitment to tight junctions by MarvelD3:
  PMID:24567356 —
  a regulatory sequestration site, kept as non-core.

Scaffolds / interactors (protein binding IPI rows)

• MAP2K4 (PMID:9808624) -> direct, functional; MODIFY to GO:0031434 MAPKK binding.
• MAP4K2/GCK (PMID:11784851) -> direct in vitro binding of kinases; MODIFY to GO:0019901 protein kinase binding.
• DCAF7/Han11 (PMID:20940704, PMID:14743216) and FLNB (PMID:19270716) are scaffolds that bind MEKK1; the
  informative function belongs to the scaffold, not MEKK1 -> REMOVE generic protein binding.
• BRAF (PMID:16810323, PMID:16888650): cached full texts do not mention MEKK1 at all (probably IntAct
  large-scale/supplementary data) -> REMOVE generic protein binding (does not mean interaction is false).

Odd annotation

• GO:0071260 cellular response to mechanical stimulus, IEP, PMID:19593445 (BAD / prostate cancer paper).
  Cached full text does not mention MEKK1/MAP3K1 or mechanical stimulation; the same PMID supports the
  same IEP term on FAS, GADD45A, MAP2K4, MAP3K2, MAPK8, TNFRSF1A, suggesting a batch UniProt annotation
  whose basis is not visible to us -> UNDECIDED.

Disease

• 46,XY DSD (SRXY6), gain-of-function-like alleles altering p38/ERK phosphorylation and RHOA binding
  PMID:21129722
• Frequent truncating mutations in luminal breast cancer (deep research, falcon).