FGFR1 (human, P11362) curation notes

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

Context: reviewed as part of the FGFR signaling module (modules/fgfr_signaling.yaml), which
models FGFR1-4 as paralog variants of one receptor tyrosine kinase step.

Core biology (with provenance)

• Receptor tyrosine kinase for FGFs: "Tyrosine-protein kinase that acts as a cell-surface receptor
  for fibroblast growth factors" [file:human/FGFR1/FGFR1-uniprot.txt].
• Ligand + HSPG induce dimerization and autophosphorylation: PMID:15863030
• Ordered trans-autophosphorylation; activation loop first: PMID:19224897; asymmetric kinase dimer PMID:20133753.
• Y653/Y654 required for kinase activation PMID:8622701.
• pY766 docks PLC-gamma1 PMID:1656221; Y766F abolishes PtdIns hydrolysis but not mitogenesis PMID:1379697.
• FRS2 binds juxtamembrane region constitutively (non-pY motif) PMID:9660748.
• Heparin: 2:2:2 FGF:FGFR:heparin complex PMID:11030354.
• Ligand specificity by splice variant: PMID:8663044.
• Signal termination: ubiquitination and lysosomal sorting PMID:18480409; NEDD4-1 PMID:21765395.

Paralog-specific points relevant to the module

• FGF23 (endocrine) via FGFR1c + alpha-Klotho: [PMID:19966287 "Fibroblast growth factor (FGF) 23
  inhibits renal phosphate reabsorption by activating FGF receptor (FGFR) 1c in a Klotho-dependent
  fashion."; "the soluble ectodomains of FGFR1c and Klotho are sufficient to form a ternary complex with
  FGF23 in vitro."]. This supports the module's FGFR1c/Klotho FGF23 variant note.
• FGF21 via FGFR1c + beta-Klotho (adipose): PMID:17623664.
  Note this paper shows FGF19/21 can signal via FGFR1-3 with beta-Klotho, so FGF21 is not strictly
  FGFR1-exclusive at the biochemical level; FGFR1c predominance is a tissue-expression effect.
  Only FGF19 (not FGF21) signals efficiently through FGFR4.
• GnRH neuron development / Kallmann (KAL2): FGFR1-specific in humans PMID:12627230; anosmin-1 (ANOS1/KAL1) binds FGFR1 with high affinity but FGFR2IIIc
  weakly and FGFR3IIIc negligibly PMID:19696444.
• Pfeiffer P252R (FGFR1) is the paralogous counterpart of Apert P253R (FGFR2) and Muenke P250R (FGFR3),
  but ligand-specificity effects differ between paralogs PMID:14613973.

Key curation decisions

• 45 protein binding IPI rows: FGF-ligand-only rows MODIFY -> GO:0017134 fibroblast growth factor
  binding; PLCG1-only rows MODIFY -> GO:0043274 phospholipase binding; everything else REMOVE as
  uninformative (HT AP-MS/BioID/PLA, HSP90 client, co-IP with cadherin/catenin, 5-HT1A, NOSTRIN, FRS2,
  NEDD4, anosmin-1, FOP-FGFR1 fusion).
• PMID:8753773 (IPI with CD24): abstract only describes CD24 with c-fgr (FGR) and lyn; possible
  FGR/FGFR1 confusion, not verifiable without full text. Removed on uninformative-term grounds only.
• MAPK cascade (TAS) and positive regulation of MAP kinase activity (IDA) -> MODIFY to GO:0043410
  positive regulation of MAPK cascade (receptor initiates, does not execute, the phosphorelay).
• identical protein binding -> MODIFY to protein homodimerization activity; homodimerization kept
  non-core (mechanistic sub-step of receptor activation).
• PMID:23382219 (signaling receptor complex, IDA): cached text is a PX-FERM cargo screen and does not
  mention FGFR1 explicitly; accepted deferring to curator since FGFR1 complex membership is well
  established.
• Developmental, endothelial (miRNA papers), EMT and 5-HT1A heteroreceptor annotations kept as non-core.
• No NEW annotations proposed. GnRH neuron development (GO:0021888) was considered but not added:
  human genetic evidence is necessity evidence and the in vivo cell-autonomous mechanism was not
  verified from cached sources.