FGF23 (human, Q9GZV9) curation notes

2026-09-30 initial review

Identity and molecular role

• Secreted endocrine member of the FGF family (FGF19 subfamily). Bone-derived (osteocytes/osteoblasts) phosphaturic hormone.
  PMID:17086194
• Receptor: alpha-Klotho (KL) + FGFR1c. Klotho converts FGFR1c into an FGF23-specific receptor.
  PMID:17086194
  PMID:16436388
• Structural basis: 1:1:1 ternary complex; alpha-Klotho tethers FGF23 C-terminal tail; dimerisation still requires heparan sulfate.
  PMID:29342138
  PMID:19966287
• Intrinsic FGFR affinity is modest without Klotho PMID:16436388.

Inactivation / processing

• Cleavage at RXXR (176-179) by proprotein convertase (furin) inactivates; GALNT3 O-glycosylation blocks cleavage; FAM20C phosphorylation of Ser180 opposes glycosylation (UniProt PTM).
  PMID:16638743
  PMID:19966287
• The cleaved C-terminal tail is a competitive inhibitor PMID:19966287.

Physiology (downstream outcomes of signalling in target cells)

• Kidney proximal tubule: reduces NaPi-2a, phosphaturia PMID:11409890; PMID:15040831.
• Vitamin D: suppresses CYP27B1, induces CYP24A1 PMID:15040831.
• Knockout: hyperphosphatemia, high 1,25(OH)2D PMID:14966565.
• Parathyroid: Klotho-dependent MAPK/EGR1 and decreased PTH secretion (rat) PMID:17992255.
• Bone (in vitro overexpression): suppresses osteoblast differentiation / mineralization PMID:18282132.
• Disease: ADHR gain-of-function (cleavage-resistant R176/R179) PMID:11062477; loss-of-function -> hyperphosphatemic familial tumoral calcinosis (UniProt).

Curation decisions (key)

• Core MF: FGF receptor binding (GO:0005104; specifically type 1 FGFR binding GO:0005105 via FGFR1c) plus hormone activity (GO:0005179). Growth factor activity (GO:0008083) is an inherited family function; FGF23 acts as hormone rather than mitogen -> kept as non-core.
• Participation vs outcome: vitamin D catabolic process (IDA) is catalysed by CYP24A1, whose expression FGF23 signalling induces -> MODIFY to regulation terms. Phosphate ion homeostasis kept (hormones are conventionally annotated to the homeostatic process they regulate).
• Protein binding IPI rows: Klotho/FGFR1 rows -> MODIFY to FGF receptor binding; SMAD4 row (high-throughput neo-PPI screen) -> REMOVE (uninformative).
• IBA cytoplasm: FGF23 has a signal peptide and acts extracellularly -> REMOVE (is_active_in cytoplasm inherited from intracellular/non-classical family members).
• IBA neurogenesis / cell migration / positive regulation of cell proliferation: paracrine-FGF functions not supported for FGF23 -> MARK_AS_OVER_ANNOTATED.
• Rat/mouse Ensembl IEA "response to X" terms (leptin, IL-6, PTH, vitamin D, magnesium, sodium phosphate) describe regulation of FGF23 expression, i.e. the gene responds as a target, not the protein's function -> MARK_AS_OVER_ANNOTATED / KEEP_AS_NON_CORE as argued per row.

Final action tally (2026-09-30)

ACCEPT 160 (of which 150 are the Reactome extracellular-region TAS rows), KEEP_AS_NON_CORE 11,
MODIFY 8, MARK_AS_OVER_ANNOTATED 8, REMOVE 2, NEW 1. No UNDECIDED.

• GO:0010966 regulation of phosphate transport (IDA) -> MODIFY to GO:2000119 negative regulation of
  sodium-dependent phosphate transport: direction and transport system are both established
  PMID:11409890, [PMID:15040831 NaPi-2a reduction].
• GO:0042369 vitamin D catabolic process (IDA) and GO:0042359 vitamin D metabolic process (IEA) ->
  MODIFY to GO:0010957 negative regulation of vitamin D biosynthetic process. FGF23 catalyses no step;
  CYP24A1/CYP27B1 do, and FGF23 regulates their expression. GO has no "regulation of vitamin D
  catabolic process" term - raised in suggested_questions.
• GO:0046888 (IEA + ISS) -> MODIFY to GO:2000829 negative regulation of parathyroid hormone secretion,
  the hormone being known PMID:17992255.
• NEW GO:0005179 hormone activity: FGF23 is a bone-derived circulating hormone; more informative than
  the inherited GO:0008083 growth factor activity, which is kept as non-core.
• propagation_review blocks added for the four IBA rows judged wrong (cytoplasm, proliferation,
  neurogenesis, cell migration), all traced to PANTHER:PTN000160075 with
  root_cause PROPAGATION_BAD.

Module relevance (modules/fgfr_signaling.yaml)

The module's endocrine_fgf_ligand annoton uses GO:0005104 for FGF23, which this review accepts. The
review additionally settles that FGF23's specific receptor term is GO:0005105 (type 1 FGFR binding,
FGFR1c) and that its distinctive molecular function is hormone activity (GO:0005179) rather than
growth factor activity - the module may wish to note the endocrine-ligand hormone activity alongside
receptor binding. No module edits made.

2026-10-10 content re-audit

All 190 rows re-checked after the status change to COMPLETE; no corrections were needed (see
history/genes/human/FGF23). The physiological axis is now modelled in
modules/fgf23_klotho_phosphate_homeostasis.yaml, using hormone activity (GO:0005179) for FGF23,
consistent with this review's core functions.