TGFBR3 (human, Q03167) notes

2026-10-21 — Full re-review, independent of the ProtNLM2 predictions

Context: reviewed as the experimentally characterised reference for the donkey
(EQUAS) TGFBR3 ortholog A0A8C4M6Z6. ProtNLM2 output was not consulted.

Deep research

just deep-research-falcon human TGFBR3 --fallback perplexity-lite failed: falcon
returned "Failed to authenticate" and the perplexity fallback returned HTTP 401
(insufficient quota). No deep-research file exists; the review is based on the cached
publications listed in the review YAML, the UniProt record, PANTHER/PAINT data and
Reactome entries.

Evolutionary grounding

• PANTHER PTHR14002 (endoglin/TGF-beta receptor type III), subfamily PTHR14002:SF7
  (TGFBR3); endoglin is a separate subfamily, so endoglin-specific functions were not
  transferred.
• PAINT node PTN002678643 (taxon Euteleostomi) IBDs: GO:0005024, GO:0005114,
  GO:0005539, GO:0050431, GO:0001837, GO:0007179, GO:0017015
  (interpro/panther/PTHR14002/PTHR14002-paint.tsv). Plasma membrane IBD comes from
  the deeper PTN008553354 node. PAINT did not propagate BMP binding, coreceptor
  activity, inhibin terms or any developmental terms; I read that as deliberate.

Experimentally established in human

• Type III TGF-beta receptor / ligand presentation and TGFBR2 binding
  PMID:11323414.
• Inhibin coreceptor with ActRII PMID:10746731.
• BMP binding and BMP signaling PMID:18184661; ALK3/ALK6 PMID:19726563.
• GIPC1 PDZ binding PMID:11546783.
• beta-arrestin 2 recruitment after TGFBR2 phosphorylation and endocytosis PMID:12958365;
  Cdc42 activation and inhibition of migration PMID:19416857; NF-kappaB inhibition
  PMID:19325136; integrin a5b1 trafficking and FN adhesion PMID:22562249.

Inferred from mouse (not human)

• Embryonic lethality with heart/liver defects PMID:12773577; coronary vessel
  formation failure PMID:17704211; epicardial EMT/invasion via GIPC and
  Par6/Smurf1/RhoA [PMID:21871877, PMID:22033038, PMID:22237159]; inhibin A (not B)
  coreceptor in gonadotropes PMID:30364975.
• Fine-grained cardiac/hematopoietic/palate ISS terms from mouse knockouts were marked
  as over-annotations (downstream phenotypes, not participation).

Key decisions

• GO:0005024 rows -> MODIFY to GO:0070123 (GO:0005024 definition implies kinase
  catalysis; betaglycan lacks a kinase domain).
• GAG/heparin binding -> MARK_AS_OVER_ANNOTATED (covalent GAG substitution is not
  GAG binding).
• Protein binding IPIs converted to informative terms (inhibin complex binding, TGF-beta
  binding, PDZ domain binding, arrestin family protein binding); FGFR4 screen hit removed.
• Cytosol (Reactome) removed: signal peptide + type I TM protein.
• Immune response IMP (SNP association) removed.
• NEW: GO:0032926 negative regulation of activin receptor signaling pathway (inhibin
  coreceptor; TGFBR3 itself forms the antagonistic complex).
• NOT JNK/ERK ISS rows and SMAD binding IMP left UNDECIDED (source evidence not
  accessible).