ICAM-3 Receptor Activity — Obsoletion & Replacement

IN_PROGRESS OBSOLETION

ICAM-3 Receptor Activity — Obsoletion & Replacement

Overview

A GO obsoletion proposal will retire GO:0030369 ICAM-3 receptor activity
(MF) and move its annotations to the parent term
GO:0004888 transmembrane signaling receptor activity, with the ligand
specified via an annotation extension has_input ICAM3 (UniProtKB:P32942) in
P2GO / GO-CAM rather than baked into a dedicated ligand-specific receptor
term.

The rationale, captured in the upstream go-ontology discussion
(geneontology/go-ontology#30560),
is that GO:0030369 is overly specific: ICAM3 is a ligand for at least three
distinct receptors (LFA-1 = ITGAL:ITGB2; the ITGAD:ITGB2 αD/β2 heterodimer;
and the C-type lectin CLEC4M / DC-SIGNR), so a single "ICAM-3 receptor
activity" MF term forces those biochemically and structurally distinct
receptors into one bucket. The proposed solution generalises to
GO:0004888 and uses the has_input annotation extension to record which
adhesion molecule each receptor actually binds. The same approach is
proposed for other singleton receptor-for-X terms under GO:0004888 that
have no further child terms.

This project tracks the impact on AI Gene Review and queues affected genes
for review, since none of the directly annotated genes are currently in this
repository.

Upstream tickets

Obsoletion plan (per upstream)

Obsoleted term ID Replacement
ICAM-3 receptor activity GO:0030369 GO:0004888 transmembrane signaling receptor activity (+ has_input ICAM3 / UniProtKB:P32942 extension)

Term status verified in OLS on 2026-05-30: GO:0030369 is still live
(isObsolete: false); the obsoletion is at the proposal stage in the
upstream ontology ticket. GO:0004888 transmembrane signaling receptor
activity is the live parent and is the proposed replacement.

Affected experimental / curated annotations

Pulled from QuickGO on 2026-05-30 (filter assignedBy=UniProt,
goId=GO:0030369). The upstream issue lists "UniProt 3" affected
annotations, all human:

# Group Gene Species UniProt Reference Evidence Status
1 UniProt ITGAL H. sapiens P20701 PMID:19029120 IMP move to GO:0004888 + has_input UniProtKB:P32942
2 UniProt ITGB2 H. sapiens P05107 PMID:19029120 IMP move to GO:0004888 + has_input UniProtKB:P32942
3 UniProt CLEC4M H. sapiens Q9H2X3 PMID:11257134 NAS move to GO:0004888 + has_input UniProtKB:P32942

ITGAL and ITGB2 are the LFA-1 αL/β2 heterodimer subunits; their joint IMP
annotation comes from a single publication (PMID:19029120). CLEC4M /
DC-SIGNR is the dendritic-cell C-type lectin; its annotation is NAS
(non-traceable author statement) and pre-dates current evidence-code
standards.

The remaining ~155 annotations to GO:0030369 in QuickGO are IEA from
Ensembl Compara orthology projection of these three human entries
(GO_REF:0000107, ECO:0000265), so they will follow the human entries
automatically once those are moved.

Mappings flagged for redirection

Upstream states None for InterPro2GO, UniProt-Keywords, and UniRule
mappings to GO:0030369. No mapping redirects are required for this
obsoletion.

Impact on this repo

No genes directly annotated to GO:0030369 are currently reviewed here.
Searches under genes/ for ITGAL, ITGB2, CLEC4M, CD209, ICAM3
(and accessions P20701, P05107, Q9H2X3, P32942) returned no matches on
2026-05-30. This means no existing reviews need refresh for the
obsoletion itself; the project is a queueing exercise that lines up
leukocyte adhesion receptors for prospective review.

The repo currently has no other ICAM-family or β2-integrin reviews, so
this would be the entry point for that area of immunology.

Scope

Candidate genes for initial review

Verify each with just fetch-gene human <gene> before starting. None are
currently in the repo.

Tier 1 — directly annotated, experimental evidence

  1. ITGAL (human, UniProt P20701) — αL integrin subunit, partners
    with ITGB2 to form LFA-1. The PMID:19029120 IMP annotation (Cox et al.
    2008 in PMC; ICAM-3-binding study) is the experimental basis for both
    subunits. LFA-1 is the textbook leukocyte adhesion / immune synapse
    integrin, so this review would seed broad leukocyte-adhesion coverage.
  2. ITGB2 (human, UniProt P05107) — β2 integrin subunit (CD18),
    common to LFA-1, Mac-1 (with ITGAM), p150,95 (with ITGAX), and αD/β2
    (with ITGAD). Loss-of-function causes leukocyte adhesion deficiency
    type I (LAD-I). The shared PMID:19029120 annotation pairs naturally
    with the ITGAL review.

Tier 2 — directly annotated, NAS evidence

  1. CLEC4M / DC-SIGNR / L-SIGN (human, UniProt Q9H2X3) — C-type
    lectin expressed on sinusoidal endothelial cells (liver, lymph node)
    and certain DCs. The GO:0030369 annotation is NAS from PMID:11257134
    and would benefit from re-evaluation against current understanding of
    DC-SIGNR as primarily a high-mannose-glycan / pathogen-recognition
    lectin (HIV, HCV, SARS-CoV-2 spike, Ebola GP) whose ICAM-3 binding is
    glycan-dependent. Core MF terms should likely centre on D-mannose
    binding (GO:0005537) and high-mannose glycan recognition, with
    ICAM3-binding captured via has_input on the signaling receptor
    activity.
  1. CD209 / DC-SIGN (human, UniProt Q9NNX6) — DC-SIGNR's closer
    paralog, expressed on dendritic cells. Listed by the upstream
    curator as one of the canonical ICAM-3 receptors but does not appear
    in the QuickGO list of direct GO:0030369 annotations as of 2026-05-30.
    A CD209 review would naturally complement CLEC4M and provide a
    cleaner template for handling glycan-dependent ICAM3 binding.
  2. ITGAD (human, UniProt Q13349) — αD integrin subunit, the
    third β2-partnered α subunit alongside ITGAL and ITGAM. Also
    mentioned upstream as forming an ICAM3-binding heterodimer with
    ITGB2. Lower priority because no direct GO:0030369 annotation, but
    inclusion would round out the β2-integrin family.
  1. ICAM3 (human, UniProt P32942) — the ligand itself, not on
    the upstream list. Its annotation profile (cell adhesion molecule
    binding, leukocyte adhesion, signaling-ligand role) is the
    complementary view of the same biology and would be a natural addition
    if leukocyte adhesion receptor coverage is built out here.

Proposed approach

  1. No urgent action needed. The upstream ontology ticket #30560 is
    still in proposal stage (OPEN, no obsoletion PR yet) as of 2026-05-30,
    and the annotation tracker #6442 was opened the day before this
    project file. Reviews can proceed on the underlying biology now using
    the live GO:0004888 term and recording the proposed has_input ICAM3
    extension; the actual obsoletion of GO:0030369 will follow once
    discussion concludes upstream.
  2. Begin with paired ITGAL + ITGB2 review. LFA-1 is the canonical
    leukocyte adhesion integrin with substantial biochemistry / structural
    biology and a well-defined disease association (LAD-I for ITGB2). The
    shared PMID:19029120 evidence makes the two reviews efficient to do
    together.
  3. Follow with CLEC4M. This is the more diagnostic review because the
    GO:0030369 annotation is NAS and the underlying biology (high-mannose
    glycan recognition, ICAM3 binding as a glycan-mediated interaction)
    may warrant MARK_AS_OVER_ANNOTATED or MODIFY to GO:0005537 +
    GO:0004888 (with has_input extension) rather than a straight
    transfer.
  4. Add CD209 if leukocyte adhesion / pathogen recognition coverage is
    built out     — it provides the cleaner template (well-characterised
    C-type lectin with multiple pathogen ligands) and complements CLEC4M.
  5. Defer ITGAD and ICAM3 itself unless interest develops; the Tier 1
    pair covers the bulk of the LFA-1 biology and the upstream obsoletion.
  6. Cross-reference with leukocyte adhesion / immune synapse work if
    such projects are added later. No related obsoletion projects in this
    repo overlap directly with the leukocyte adhesion receptor area.

Priority

Low-medium. The biology is canonical and well-established, the
upstream obsoletion has not yet been implemented (proposal stage), and
no existing reviews in this repo are blocked by the obsoletion (no
ITGAL / ITGB2 / CLEC4M / CD209 reviews exist yet). This is opportunistic
— LFA-1 (ITGAL + ITGB2) is a major unreviewed leukocyte adhesion
receptor, so the obsoletion is a reasonable trigger to start that
coverage if interest develops. The CLEC4M NAS-evidence review is the
most diagnostically interesting piece because the underlying biology
may not match the literal "ICAM-3 receptor" framing.

Status