MAP2K1 (MEK1, human, UniProt Q02750) — curation notes

Identity and family

• Dual-specificity MAP kinase kinase 1; STE Ser/Thr kinase family, MAP kinase kinase subfamily
  [file:human/MAP2K1/MAP2K1-uniprot.txt "Belongs to the protein kinase superfamily. STE Ser/Thr"].
• PANTHER (UniProt DR line): PTHR47448:SF2 "MITOGEN-ACTIVATED PROTEIN KINASE KINASE 1". The IBA rows
  descend from PAINT node PANTHER:PTN000684494 (listed in WITH/FROM of the IBA rows). Note that
  modules/erk_cascade.yaml declares PTHR48013 for the MEK1/MEK2 tier; the repo's PANTHER member index
  (interpro/panther/panther-members.tsv) places Q02750 in PTHR48013:SF5, consistent with the module. The
  cached UniProt DR line lists PTHR47448:SF2, reflecting a different PANTHER release (no action needed).
• Paralog: MAP2K2/MEK2 (P36507); the two are the only ERK1/2-specific MAP2Ks.

Core molecular function

• MEK1 catalyses concomitant Thr and Tyr phosphorylation of the ERK1/ERK2 TEY activation motif
  [file:human/MAP2K1/MAP2K1-uniprot.txt "concomitant phosphorylation of a threonine and a tyrosine residue in a"];
  "function specifically in the MAPK/ERK cascade".
• Reactome: [Reactome:R-HSA-109860 "MAP2K1 (also known as MEK1) phosphorylates the critical Thr202 and Tyr204 on MAPK3 (ERK1), converting two ATP to ADP."]
• Original cloning: recombinant MEK1 activates human ERK1 in vitro
  PMID:8388392
• Reconstituted assays with purified ERK2, MEK1 variants and ATP PMID:28166211.
• Coupled RAF->MEK1->ERK2 assays PMID:10644344.
• Substrate specificity is very narrow: ERK1/2 are the established physiological substrates
  (deep research, falcon; citing Barbosa et al. 2021 review).

Regulation

• Activated by RAF (and MOS, MEKK1 etc.) phosphorylation of Ser218/Ser222
  [file:human/MAP2K1/MAP2K1-uniprot.txt "Activation occurs through phosphorylation of Ser-218"].
• ERK negative feedback on MEK1-specific Thr292 [Reactome:R-HSA-5674496 "phosphorylating MAP2K1 at T292, a residue that is not present in MAP2K2"].
• CDK1 phosphorylation (Reactome:R-HSA-112342), anthrax lethal factor cleaves the N-terminal docking site (Reactome:R-HSA-5211340).

Non-catalytic role: allosteric BRAF activation via KSR

• MEK1 binding to KSR1/2 releases KSR autoinhibition and drives KSR–BRAF heterodimerization, independent of MEK catalysis
  PMID:29433126;
  PMID:29433126.
• This is the basis for UniProt's IMP "MAP kinase scaffold activity" (GO:0005078) and for GO:0043539
  "protein serine/threonine kinase activator activity" being biologically defensible for MEK1 (as a non-catalytic activator of BRAF).
• BRAF–MEK1 face-to-face complex PMID:25155755.

Scaffolds / partners (for protein-binding MODIFY decisions)

• KSR1 (scaffold) PMID:10409742 -> GO:0097110 scaffold protein binding.
• RAF1/BRAF/MOS (MAP3Ks) -> GO:0031435 MAPKKK binding (consistent with MAP2K2 review).
  MOS: PMID:34779126.
• ERK1/ERK2 (substrates and cytoplasmic anchoring) -> GO:0051019 mitogen-activated protein kinase binding.
  PMID:17255949.
• VRK2A anchors KSR1–MEK1 at the ER PMID:22752157.
• PPARG: MEK1 binds and exports PPARG from nucleus PMID:17101779.
• Other partners (TRIB1/3, CFLAR, BIRC6, PIN1, YAP1, BTRC, BANP, TCP11, PLEKHF2) come from single studies or
  binary/AP-MS screens; no informative MF term can be derived -> REMOVE generic protein binding (interaction not disputed).

Localization

• Predominantly cytoplasmic/cytosolic, with NES-driven nuclear export; shuttles into the nucleus on stimulation
  PMID:17101779.
• Peripheral membrane via KSR PMID:10409742.
• Centrosome / spindle pole / midbody during mitosis (UniProt SubCell from PMID:14737111).
• Endosome (LAMTOR3/MP1 scaffold; Reactome R-HSA-5674132, R-HSA-5674130), Golgi (IL17RD/Sef; R-HSA-5674373), ER (VRK2).
• Mitochondrion, focal adhesion: only TAS from a review (PMID:19565474, abstract only) and ARBA; left UNDECIDED.

Miscitation found

• GOA rows (MGI, 2014) "protein binding" IDA and "endoplasmic reticulum" IDA cite PMID:22572157, which is a
  platelet-alloantibody biosensor paper with no MEK1 content. PMID:22752157 (VRK2 anchors KSR1-MEK1 to ER)
  differs by a two-digit transposition (57<->75) and exactly matches both claims (ER; MEK1–KSR1–VRK2 complex).
  The same PMID:22572157 is also on CALR and CANX in this repo (MGI, likely ER markers in the same paper).
  Recorded as WRONG_IDENTIFIER with replacement PMID:22752157 (inferred, not confirmed by MGI).
• PMID:19593445 (the known batch miscitation) is NOT among MAP2K1 GOA rows.

Processes

• Core: ERK1 and ERK2 cascade (GO:0070371) / MAPK cascade (GO:0000165).
• MEK1-specific (not MEK2) role in G2 Golgi fragmentation and mitotic entry via Myt1
  PMID:23241949 -> Golgi inheritance kept non-core.
• Oncogene-induced senescence with constitutively active MEK1 (PMID:9765203; only title cached).
• Many rat-derived (Q01986) IEA process terms are pharmacological (MEK inhibitor) readouts downstream of ERK
  (muscle contraction, glucocorticoid response, triglyceride homeostasis, etc.) -> over-annotation.
• Mouse-derived (P31938) Schwann cell / myelination / ERBB / NMJ terms come from Mek1/2 conditional knockout genetics
  -> non-core developmental roles via ERK signaling.

Disease

• Germline activating variants: cardiofaciocutaneous syndrome 3 (CFC3); somatic mosaic: melorheostosis; somatic cancer
  alleles in three RAF-dependence classes (deep research, Gao et al. 2018).

Earlier independent review on main (commit c65068660)

MAP2K1 was reviewed independently on main (commit c65068660) while this review was in progress. When PR #3381 was merged with main (2026-10-08), this review was kept as canonical because it is COMPLETE and re-types bare protein-binding rows to informative terms where the other review removed them; the other review added no rows, questions or terms that this one lacked. Its notes are preserved below for provenance; its deep-research file is in git history at c65068660.

MAP2K1 curation notes

2026-09-30 PENDING annotation review

Provider deep research was unavailable for this seeded MAP2K1 pass: Falcon required
agentapi on PATH in the parent environment, and the Perplexity/OpenAI fallbacks
lacked API keys. This pass relied on the UniProt record, GOA-seeded review rows,
cached PMID records, and cached Reactome summaries where present.

2026-11-03 ORGANELLES batch 4 (mitochondrion rows)

Rows: GO:0005739 IEA (GO_REF:0000117, ARBA:ARBA00026962) and TAS (PMID:19565474), both located_in, both
UNDECIDED before. No sub-compartment rows.

Checks:
- ARBA00026962 (UniProt REST, 2026-11-03) pools condition sets from unrelated families; MEK1 matches the
IPR000719 + IPR050915 (MAP kinase kinase) set in Euarchontoglires. Unvetted, not used as support.
- QuickGO: rodent orthologs carry only the same ARBA and TAS rows; no experimental MEK row to project from.
- TAS source PMID:19565474 (Yao and Seger 2009 review) is abstract-only and never says "mitochondri".
- Primary studies fetched: PMID:18545666 (Galli 2008, full text) PMID:18545666, in mouse cells PMID:18545666; fraction purity by complex I/IV, LDH and PI only (no ER marker).
PMID:15030409 (Alonso 2004, rat brain, abstract-only) PMID:15030409.
- Both use MEK1/2 antibodies, so MEK1 cannot be separated from its paralog.

Outcome: both rows UNDECIDED -> KEEP_AS_NON_CORE (minor, transient signalling pool with the ERK module;
TRAF3/BRAF precedent). Stays at root: no transit peptide or anchor, sub-mitochondrial data split between OMM
and IMS. Added PMID:18545666 and PMID:15030409 to references.