MAPK3 (ERK1, P27361) curation notes

Identity and core molecular function

• MAPK3 encodes ERK1/p44-MAPK, a CMGC-family proline-directed Ser/Thr kinase; the
  paralog MAPK1 encodes ERK2/p42. [file:human/MAPK3/MAPK3-deep-research-falcon.md
  "MAPK3 is an ATP-dependent, proline-directed protein serine/threonine kinase."]
• UniProt function: [file:human/MAPK3/MAPK3-uniprot.txt "Serine/threonine kinase which
  acts as an essential component of the MAP kinase signal transduction pathway"]
• Activation by MEK1/2 on the TEY motif: [file:human/MAPK3/MAPK3-uniprot.txt
  "Phosphorylated by MAP2K1/MEK1 and MAP2K2/MEK2 on Thr-202 and Tyr-204 in response to
  external stimuli like insulin or NGF. Both phosphorylations are required for activity."]
• Direct biochemical evidence with human ERK1: PMID:8388392; cloned human erk1 has MBP kinase activity
  PMID:7687743.
• ERK1-specific substrate evidence: DEPTOR S235 PMID:35216969; MED1 PMID:18391015; PARP1 PMID:16627622; PD-1 PMID:37208329.
• Autophosphorylation is minor/in vitro only: PMID:7687743; [file:human/MAPK3/MAPK3-deep-research-falcon.md "ERKs have negligible
  basal/autophosphorylation activity under ordinary conditions and normally depend on
  upstream MAP2Ks."] -> peptidyl-tyrosine autophosphorylation treated as over-annotation.

Localization

• Dynamic cytoplasm/cytosol <-> nucleus shuttling; resting cells cytoplasmic
  [file:human/MAPK3/MAPK3-deep-research-falcon.md "In resting cells, ERK is commonly
  cytoplasmic because of anchoring by MEK and proteins such as PEA-15."].
• Nuclear accumulation on stimulation [file:human/MAPK3/MAPK3-uniprot.txt
  "Autophosphorylation at Thr-207 promotes nuclear localization"].
• ERK1-specific (rat ortholog) caveola and focal adhesion (GIT1-dependent) are in UniProt;
  kept as non-core. Endosome/Golgi/mitochondrion/cytoskeleton rows come from the Yao &
  Seger 2009 review (PMID:19565474) and ARBA rules; these are compartment-restricted pools,
  treated as over-annotations, consistent with MAPK1 review.
• Nuclear envelope IDA (PMID:20455999) is an insulin/caveolin-2-specific event
  ["insulin-activated extracellular signal-regulated kinase (ERK) is translocated to the
  nuclear envelope by caveolin-2 (cav-2)"] -> non-core.

Processes

• Core: ERK1 and ERK2 cascade (GO:0070371) / MAPK cascade, protein phosphorylation,
  intracellular signal transduction.
• Many downstream process rows rely on pan-ERK1/2 inhibitors (PD98059, U0126) or phospho-ERK
  readouts, not ERK1-specific perturbation [file:human/MAPK3/MAPK3-deep-research-falcon.md
  "pan-ERK inhibition or total ERK output should not be reannotated as MAPK3-specific"].
  These are kept as non-core or marked as over-annotated.
• IEA transfers from mouse Erk1 (Q63844 / ENSMUSP00000051619): mouse Erk1-null data
  underlie myelination/Schwann cell, pain, synaptic transmission, cholesterol efflux; kept
  as non-core (consistent with mouse Mapk3 review).
• PMID:11096076 (QRS-ASK1, glutamine deprivation) abstract does not mention ERK; IDA rows
  for amino acid starvation set UNDECIDED; stress-activated MAPK cascade is a JNK/p38 term
  and marked over-annotated.
• PMID:24854121 is a BBB permeability paper; it supports EGFR-ERK1/2 signaling but the
  abstract does not discuss neuroinflammation -> positive regulation of neuroinflammatory
  response IDA set UNDECIDED.
• PMID:21531765 RNAi telomerase screen highlights ERK8 (MAPK15) in abstract; MAPK3 row kept
  as over-annotation (full text not available).
• PMID:19593445 (BAD / prostate cancer): documented batch miscitation for GO:0071260
  (see projects/MISCITATIONS.md) -> UNDECIDED; reference relevance NONE, MISCITED.

Protein binding (GO:0005515) policy

Replacement MF terms follow the MAPK1 review choices:
- phosphatases (DUSP1, DUSP6, PTPRR, PTPRB, PTPRJ) -> GO:0019903 protein phosphatase binding
[file:human/MAPK3/MAPK3-uniprot.txt "Dephosphorylated by PTPRJ at Tyr-204."]
- kinases (MAPK14, DAPK1) -> GO:0019901 protein kinase binding
- MAP2K1 -> GO:0031434 mitogen-activated protein kinase kinase binding
- transcription factors (ELK1, HSF1, KLF4, ZNF263) -> GO:0140297
- scaffolds (PEA15, SCRIB) -> GO:0097110 scaffold protein binding
- substrates/high-throughput partners without an informative MF (DHPS, TPR, RPS3, Eps8,
Nsmf/Jacob, PKM, CDKN2AIP, PNKD, UNG, FAM135B, OTUD7B, MRFAP1L1, KLHL32, CD248, PADI3)
-> REMOVE (removal does not mean the interaction is false).

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
MARK_AS_OVER_ANNOTATED before. No sub-compartment rows.

Checks:
- ARBA00026962 is a multi-family association rule without its own evidence; not used as support.
- TAS review PMID:19565474 is abstract-only and does not mention mitochondria.
- Direct human ERK1 evidence, PMID:19847302 (Galli 2009, HeLa, full text): PMID:19847302;
PMID:19847302; ER contamination
checked PMID:19847302. Serum stimulation moves ERK1 out towards the nucleus. Histone partners placed at the OMM by
proteinase K; the discussion speculates about matrix/TFAM.
- Rodent ERK1/2 antibody data: PMID:18545666 (OMM and IMS subfractions), PMID:15030409 (OMM/IMS fraction).

Outcome: both rows MARK_AS_OVER_ANNOTATED -> KEEP_AS_NON_CORE. Stays at root (transient trafficking,
disagreeing sub-mitochondrial lines). References added: PMID:18545666, PMID:15030409, PMID:19847302.