ITGAM (CD11b; integrin alpha-M; CR3 alpha chain) - review notes

Provenance note: provider deep research for this gene FAILED (Falcon returned
HTTP 402 Payment Required; Perplexity is not configured in this environment). No
ITGAM-deep-research-<provider>.md file exists. The synthesis below replaces it and
was written manually from the UniProt record (P11215), the GOA annotation set, and
cached publications in publications/ (fetched with just fetch-gene-pmids /
just fetch-pmid). Quotes are verbatim from the cached files.

Identity and structure

• UniProt P11215, ITGAM_HUMAN; integrin alpha chain family; single-pass type I
  membrane protein with an inserted von Willebrand factor A-like I (alphaI/A) domain.
  PMID:2563162
• Pairs non-covalently with ITGB2 (CD18) to form integrin alphaM-beta2 (Mac-1,
  complement receptor 3, CR3). PMID:2563162
• Expression: monocytes, macrophages, granulocytes, microglia, NK and minor B/T subsets.
  PMID:8485905

Core molecular function: complement (iC3b) receptor

• The alphaM I-domain is the iC3b binding site; binding is divalent-cation dependent.
  PMID:7524101
• Structural basis: the C3d moiety of iC3b binds the CR3 alphaI domain; explains
  selectivity for iC3b over C3b. PMID:24065820
• Function: recognition and phagocytosis of iC3b-opsonised particles.
  PMID:24065820
• Human genetic evidence for the phagocytic receptor role: lupus-associated R77H
  (rs1143679) reduces iC3b-mediated phagocytosis. PMID:22586164; association with SLE PMID:18204448.
• Implication: the ligand of CR3 is a fragment of C3 (iC3b), which is deposited on
  targets by complement activation; CR3 is the receptor/effector, not a complement
  activator.

Adhesion receptor function

• Counter-receptor for ICAM-1 (neutrophil-endothelial adhesion). PMID:1980124
• Other cellular counter-receptors: JAM-3/JAM-C PMID:12208882;
  Thy-1 PMID:15004192; ECM protein TGFBIp PMID:18083624; pleiotrophin
  PMID:28939773.
• Ligand promiscuity is a known property. PMID:15194813
• Activation dependence (kindlin-3): PMID:19234460

Signaling / neutrophil activation

• CD177 (NB1)-PR3 signalling complex uses Mac-1 as transmembrane adaptor; required for
  ANCA-triggered degranulation and superoxide. PMID:21193407; lipid rafts PMID:21193407
• CD11b/CD18 promotes phagocytosis-induced neutrophil apoptosis (mouse KO).
  PMID:8986723

Microglia / CNS (mouse data; basis of ISS annotations)

• Developmental synapse pruning: microglia engulf C3-tagged retinogeniculate inputs via
  CR3. PMID:22632727
  CR3 KO yields eye-specific segregation defects (vertebrate eye-specific patterning).
• Disease models (Alzheimer mice): oligomeric Abeta-induced synapse engulfment requires CR3.
  PMID:27033548
• Fibrillar Abeta uptake/clearance partly through C3 and Mac-1. PMID:22438044; anti-CD11b reduces uptake of
  Abeta-coated particles PMID:20199584. Direct Abeta binding by CR3 is not shown
  in these abstracts.
• Developmental hippocampal neuronal death and microglial superoxide require CD11b and
  DAP12. PMID:18685038
• MPTP Parkinson model: MAC1 KO reduces microgliosis, superoxide, p47phox translocation.
  PMID:18981141. These are downstream/indirect
  phenotypes; dopamine metabolism and protein targeting terms derived from this are
  over-interpretations.

Curation conclusions (summary)

• Core: CR3 iC3b receptor (contributes to complement component iC3b receptor
  activity as the alphaM subunit; directly binds iC3b via alphaI domain), mediating
  recognition/phagocytosis of complement-opsonised targets, including C3-tagged
  synapses by microglia.
• Core: adhesion receptor for ICAM-1 and other counter-receptors, leukocyte adhesion to
  activated endothelium, cell-matrix adhesion (fibrinogen, TGFBIp).
• Remove: generic protein binding (HuRI Y2H hits among ER/membrane proteins; others are
  better captured as cell adhesion molecule binding), Ensembl rat-projected "response
  to X" terms, ARBA gross anatomical development term.
• C3b binding (ISS) should become iC3b binding (CR3 selectivity for iC3b).