FGFR3 (human, P22607) curation notes

2026-09-30 initial review (claude-code)

Identity and core biology

• FGFR3 is a single-pass type I receptor tyrosine kinase of the FGFR family
  (EC 2.7.10.1): three Ig-like ectodomains (D1-D3), TM helix, split tyrosine
  kinase domain [file:human/FGFR3/FGFR3-uniprot.txt "Tyrosine-protein kinase that acts as a cell-surface receptor"].
• Ligand (FGF) + heparan sulfate binding drives dimerization and trans-autophosphorylation
  [file:human/FGFR3/FGFR3-uniprot.txt "Ligand binding leads to dimerization and activation by"];
  PMID:11294897.
• Structural: FGF1-FGFR3c crystal structure; D1/D1-D2 linker autoinhibit FGF and heparin binding
  PMID:14732692.
  TM-domain dimer PMID:24120763;
  kinase trans-phosphorylation captured in crystal PMID:23972473.
• Ligand specificity: engineered BaF3 mitogenic assays of all FGFR splice variants
  PMID:8663044.
• Downstream: FRS2/GRB2/SOS -> RAS-ERK; PLCG1; PI3K; STAT1/3 (STAT activation by activated receptor)
  PMID:10918587;
  PMID:11294897.

Paralog-specific physiology: growth restraint in the growth plate

• Fgfr3 knockout mice show skeletal overgrowth with expanded proliferating and hypertrophic
  chondrocyte zones PMID:8601314.
• Gain-of-function human alleles (ACH, HCH, TD1/2, SADDAN) -> dwarfism; partial LOF (CATSHL) -> tall stature
  PMID:20582225.
• STAT1 arm inhibits chondrocyte proliferation; ERK arm inhibits differentiation
  PMID:15748888.
• Chondrocyte apoptosis via PLCgamma-STAT1 PMID:17561467.
• The context-dependence matters for GO: in BaF3/NIH3T3/myeloma the receptor is mitogenic
  (positive regulation of proliferation), whereas in growth-plate chondrocytes it is anti-proliferative.
  Proliferation-positive rows are therefore kept, but as non-core.

Localization

• PM is the site of function. ER/Golgi reflect biosynthetic maturation (N-glycan becomes Endo H
  resistant in Golgi) and ER retention of severe mutants PMID:17561467; vesicles reflect
  post-activation internalization [file:human/FGFR3/FGFR3-uniprot.txt "intracellular vesicles after internalization of the autophosphorylated"].
• Isoform 3 (FGFR3deltaTM) is secreted [file:human/FGFR3/FGFR3-uniprot.txt "[Isoform 3]: Secreted."].
• PMID:18061161 (FGFRL1 paper) is abstract-only in cache; the FGFR3 IDA rows (PM, Golgi, transport
  vesicle) presumably come from FGFR3 used as comparator in the full text. Not verifiable; plausible,
  so deferred to curator (not removed).

Decisions

• 313 protein binding IPI rows: 300 from one Y2H neurodegeneration interactome (PMID:32814053),
  plus HSP90AB1/CDC37 chaperone-client captures, BioPlex, RTK BioID, IgSF ELISA. All REMOVE as
  uninformative, except FGF1 (PMID:14732692), MODIFY -> GO:0017134 fibroblast growth factor binding.
• JAK-STAT (GO:0007259) MODIFY -> GO:0097696 receptor signaling pathway via STAT: STAT activation by
  FGFR3 is receptor-driven (and PLCgamma-dependent in chondrocytes), JAK involvement not shown in cited paper.
• MAPK cascade TAS -> MODIFY to positive regulation of MAPK cascade (receptor is upstream, not a cascade component).
• chondrocyte proliferation TAS -> MODIFY to negative regulation of chondrocyte proliferation (GO:1902731).
• chondrocyte differentiation TAS -> MODIFY to negative regulation of chondrocyte differentiation (GO:0032331).
• focal adhesion (colocalizes_with, TAS from review PMID:15748888, abstract-only; abstract silent) -> UNDECIDED.
• NEW: heparin binding (GO:0008201), measured by SPR in PMID:14732692.
• No NEW process terms proposed; the growth-restraint role is already captured by existing
  rows after MODIFY (GO:1902731, GO:0032331) and GO:0048640 (ISS).

Module relevance (modules/fgfr_signaling.yaml)

• Module FGFR3 variant asserts GO:0005007 at plasma membrane: consistent with this review.
• Paralog-distinguishing biology to note: FGFR3 is the growth-plate brake (negative regulation of
  chondrocyte proliferation/differentiation, negative regulation of developmental growth) and
  signals to STAT1 (PLCgamma-dependent) to induce chondrocyte growth arrest/apoptosis;
  also required for inner-ear development (CATSHL hearing loss).

2026-11-05 ORGANELLES ER batch 2 (endoplasmic reticulum rows)

Rows: GO:0005783 IDA (GO_REF:0000052, HPA immunofluorescence) and IEA (GO_REF:0000044, SL-0095), both located_in; no ER sub-compartment rows.

• UniProt: "[Isoform 1]: Cell membrane; Single-pass type I membrane protein. Cytoplasmic vesicle. Endoplasmic reticulum." (no evidence tag); curated PTM: "N-glycosylated in the endoplasmic reticulum. The N-glycan chains undergo further maturation to an Endo H-resistant form in the Golgi apparatus." (ECO:0000269 from PMID:11703096, 16410555, 17311277, 17509076).
• PMID:17561467 (abstract): PMID:17561467 Mutant retention, supportive only.
• Outcome: both rows KEEP_AS_NON_CORE held (direct IF of the endogenous protein, rule 2; biosynthetic pool of the wild type). No NEW ER membrane row: a type I receptor in transit. The UniProt ER line sits under isoform 1, the displayed isoform the row is made on, so no isoform source defect.