ANXA1 (Annexin A1; lipocortin 1) review notes
UniProt: P04083. Human, NCBITaxon:9606. PANTHER PTHR10502:SF17 (ANNEXIN A1).
Deep research status
- 2026-10-05:
just deep-research-falcon human ANXA1 failed with Edison API
429 Too Many Requests (no perplexity key available for fallback). Retried once; the retry timed out after 600 s.
No deep-research file existed for ANXA1 at review time. Update: the falcon run in
fact completed late (end 01:34) and ANXA1-deep-research-falcon.md is now present; see
"Reconciliation with late falcon deep research" below.
Review proceeds from cached GOA-cited publications, the UniProt record and a few
additional PubMed-retrieved papers (PMID:19104500, PMID:12475898, PMID:32272059,
PMID:10673436, PMID:8425544, PMID:9425121), fetched with just fetch-pmid.
Molecular properties
- Classical annexin: N-terminal ~40 aa unique domain + four ~70 aa annexin repeats
(IPR001464, IPR018502); ANXA1-specific IPR002388.
- Calcium binding and Ca2+-dependent binding to anionic phospholipids
[UniProt P04083 "Displays Ca(2+)-dependent binding to phospholipid membranes"].
- Ca2+ requirement lowest for phosphatidic acid, then PS, then PI; no PC binding
PMID:2138016
- Placental transglutaminase-crosslinked dimer also binds PS vesicles
PMID:2532504.
- Promotes aggregation and fusion of liposomes in vitro
PMID:2138016.
- N-terminal tail binds S100A11 (S100C) in Ca2+-dependent manner; heterotetramer model
PMID:8557678
PMID:10673436.
- Substrate of EGFR kinase, PKC; transglutaminase cross-linking on Gln18
PMID:3013422.
- Cleaved by cathepsin G to release the bioactive N-terminal Ac2-26 peptide
PMID:22879591.
"Phospholipase A2 inhibitor" history
- Originally cloned as a glucocorticoid-induced PLA2 inhibitor
PMID:2936963.
- The in vitro inhibition is now generally explained by substrate (phospholipid
interface) sequestration rather than direct enzyme binding
PMID:9425121;
UniProt: "Inhibition of phospholipase activity is mediated via its phospholipid binding activity that limits the access of phospholipase to its substrates."
- Conclusion: the GO MF "phospholipase A2 inhibitor activity" (binds to and inhibits
the enzyme) over-states the mechanism; not chosen as a core function.
- ANXA1 N-terminal peptides are FPR ligands on human neutrophils, inhibit
transendothelial migration PMID:10882119
- Ac2-26 activates FPR1, FPR2 (FPRL1) and FPR3 (FPRL2); chemotaxis then desensitisation
PMID:15187149
- Inhibits ACTH exocytosis via FPR and Rho kinase / actin polymerisation
PMID:19625660.
- Secreted in EVs from intestinal epithelium, promotes wound repair
PMID:25664854.
- Leaderless secretion via TMED10 channel into ERGIC PMID:32272059
(ANXA1 is named as a cargo in the UniProt record citing this paper).
- Externalised from neutrophil gelatinase granules on adhesion
PMID:10772777
Anti-inflammatory / pro-resolving physiology
- Glucocorticoid effector PMID:19104500
- Knockout mice: exaggerated inflammation, increased leukocyte emigration and IL-1beta,
glucocorticoid resistance, phagocytosis anomalies
PMID:12475898
- Bone-marrow neutrophil clearance by macrophages requires AnxA1
PMID:21957127
- Apoptotic-cell surface ANXA1 suppresses macrophage IL-8/MIP-2 PMID:22056994.
Adaptive immunity
- Recombinant ANXA1 enhances TCR signalling, IL-2, proliferation, Th1 skewing
PMID:17008549. Non-core, context dependent.
Other reported roles (non-core)
- Cornified envelope component of oral keratinocytes PMID:10908733.
- Endothelial migration downstream of VEGF, regulated by miR-196a PMID:22773844.
- Co-occupies SNX3/ANXA2-positive endosomes PMID:18767904.
- NEMO/RIP1 interaction and NF-kB activity in breast cancer cells PMID:21383699.
- Many HDA proteomic detections: exosomes, tears, ECM, focal adhesion, E-cadherin interactome.
Curation decisions summary
- Core MF: calcium-dependent phospholipid binding (PS), receptor ligand activity (FPR agonist).
- Core BP: negative regulation of inflammatory response / regulation of leukocyte
migration via FPR (GPCR) signalling.
- Generic protein binding IPI rows: REMOVE per project policy (uninformative); S100A11
binding proposed as NEW GO:0044548 S100 protein binding.
- GO:0007187 (GPCR signalling coupled to cyclic nucleotide second messenger): FPR signalling
is Gi/Ca2+/MAPK; generalise to GO:0007186.
- No GO-CAM model in gocams/index.tsv contains P04083.
Reconciliation with late falcon deep research (2026-10-05)
ANXA1-deep-research-falcon.md (Edison, 58 citations) arrived after the review was
drafted. Compared against the review:
- Consistent: Ca2+-dependent anionic phospholipid binding; extracellular FPR2/ALX
(and FPR1 for Ac2-26) agonist driving resolution of inflammation; S100A11 binding via
N-terminus; nonclassical secretion (granules, EVs); PLA2 "inhibition" is regulatory, not
catalytic. No contradiction of any review action.
- Material addition, verified and acted on: ANXA1 with ER-associated S100A11 tethers
ER-multivesicular body membrane contact sites in HeLa cells; depletion reduces contacts,
prolongs EGFR phosphorylation and impairs ILV formation and ER-to-MVB cholesterol supply
PMID:27270042.
PubMed-verified, full text cached. Added as a NEW located_in GO:0140284
(endoplasmic reticulum-endosome membrane contact site, IDA). Sterol transfer itself is by
ORP1L/VAP, so no lipid-transport term was proposed for ANXA1.
- Not adopted: deep research cites a 2007 review for direct ANXA1-cPLA2 interaction;
this conflicts with the substrate-depletion consensus already recorded above and was not
verified against primary data; the PLA2-inhibitor decisions stand.
- Noted only (not annotated): Cooray 2013 PNAS (FPR2 homodimer, p38-MAPKAPK-HSP27,
IL-10 in monocytes); PDLIM7 binding in adipogenesis (Fang 2024); platelet activation by
Ac2-26 via Fpr2/3 in mouse (2023); 2024 clinical association studies. These are
context-specific or unverified here and would not change core functions.
- Deep-research file added to
references as file:human/ANXA1/ANXA1-deep-research-falcon.md.