FGFR4 (P22455) curation notes

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

Identity and architecture

• Single-pass type I receptor tyrosine kinase; three Ig-like domains, TM, split tyrosine kinase domain (UniProt P22455).
• Unlike FGFR1-3, FGFR4 has no IIIb/IIIc alternative exon pair; its D3 is a single c-type-like configuration
  [file:human/FGFR4/FGFR4-deep-research-falcon.md "Unlike FGFR1–3, FGFR4 has one principal IgIII configuration rather than alternatively spliced b/c isoforms"].
  (Machine-generated summary; consistent with UniProt listing only isoform 1 and a soluble isoform 2.)
• Isoform 2 (P22455-2) is a soluble/secreted form (UniProt SUBCELLULAR LOCATION [Isoform 2]: Secreted) -> basis of IEA extracellular region.

Molecular function

• FGF receptor tyrosine kinase: binds canonical FGFs with heparan sulfate (Ornitz 1996 BaF3 mitogenic panel)
  PMID:8663044.
• Autophosphorylation of activation-loop tyrosines (Tyr642/643) PMID:18670643.
• Endocrine FGF19: FGFR4-selective ligand PMID:10525310;
  requires beta-Klotho (KLB) coreceptor PMID:17627937;
  at physiological pM concentrations also requires sulfated GAGs PMID:21653700.
• FGF19 vs FGF21: both bind KLB-FGFR4 but only FGF19 signals efficiently PMID:17623664.
• FGF19 residues 38-42 confer FGFR4 activation / hepatocyte proliferation PMID:20018895.

Physiological process: bile acid synthesis (core)

• Enterohepatic FXR -> FGF15/19 -> hepatic KLB-FGFR4 -> ERK -> CYP7A1 repression.
  PMID:12815072
  PMID:17623664
  PMID:19085950
  PMID:20683963
• Direction is NEGATIVE regulation of bile acid biosynthesis (GO:0070858); GOA carries the parent GO:0070857.
  FGFR4 is the signal-transducing kinase that does the work (not a substrate), so the participation test is satisfied; KLB review also uses GO:0070858.

Trafficking: recycling vs degradation (module relevance)

• Deep research summary: FGFR4 preferentially recycles (Rab11) after FGF1 stimulation, while FGFR1-3 go to lysosomes
  [file:human/FGFR4/FGFR4-deep-research-falcon.md "This recycling route, mediated by Rab11, returns FGFR4 to the plasma membrane and is associated with sustained signaling"].
• BUT the primary paper in the cache shows ligand-induced degradation of wild-type-like FGFR4-Gly388 in 293T cells, with Arg388 much more stable
  PMID:18670643,
  and MT1-MMP drives FGFR4-G388 degradation PMID:20798051.
• Conclusion: "recycles rather than being degraded" is a relative statement (FGFR4 recycles more than FGFR1-3 in the FGF1-uptake assays);
  FGFR4 is still subject to ligand- and partner-dependent degradation, allele-dependent. UniProt: "FGFR4 signaling is down-regulated by receptor internalization and degradation".
• The primary recycling paper (Haugsten et al. 2005) is not cached here; I could not reach PubMed eutils from this container to look up its PMID, so it is not cited.

Biosynthesis / glycosylation

• KLB (ER-resident per Triantis) binds core-glycosylated FGFR4 and sends it to proteasome
  PMID:20683963.
• Immature FGFR4 at Golgi, ligand-independent STAT1 phosphorylation there PMID:17311277.

Cancer / variant biology (non-core)

• G388R (rs351855) risk allele: increased stability, sustained activation, MT1-MMP stabilisation, invasion [PMID:20798051, PMID:20876804, PMID:18670643].
• FGF19-FGFR4 drives hepatocyte proliferation/HCC PMID:20018895.

Annotation issues found

• GO:0010628 positive regulation of gene expression (IMP, PMID:19085950): the only FGFR4 perturbation in that paper shows FGFR4 is needed for
  REPRESSION of CYP7A1 -> MODIFY to GO:0010629 negative regulation of gene expression.
• NOT GO:1903412 response to bile acid (IMP, PMID:19085950): paper shows CDCA increases FGFR4 tyrosine phosphorylation and FGFR4 siRNA blunts FXR-agonist
  repression of CYP7A1; the only negative observation is unchanged total FGFR4 protein. Negation not supported -> REMOVE (flag for curator).
• PMID:18061161 (FGFRL1 paper) IDA to FGFR4 for PM/Golgi/transport vesicle; abstract only mentions FGFRL1. Per rules: do not REMOVE.
  PM ACCEPT; Golgi KEEP_AS_NON_CORE (independently supported by PMID:17311277); transport vesicle UNDECIDED.
• PMID:18480409 (FGFR1 ubiquitination) IDA for FGFR4 FGFR activity / FGF binding / heparin binding / signaling. Abstract only (PMC full text not retrievable);
  UniProt cites this paper for FGFR4 catalytic activity and ubiquitination, so FGFR4 was presumably assayed in the full text. Functions are clearly correct -> ACCEPT.
• 6 generic protein binding IPIs -> REMOVE (uninformative; interactions KLB, MMP14, FGFR1, RET, SDC2, TGFBR3 not denied).

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

Rows: GO:0005783 IDA (PMID:20683963) and IEA (GO_REF:0000044, SL-0095), both located_in; no ER sub-compartment rows; no is_active_in.

• FGFR4 is a single-pass type I receptor (UniProt FT SIGNAL 1..21, TRANSMEM 370..390), with no ER retention motif. The ER is its biosynthetic route.
• PMID:20683963 (abstract only, no PMC): PMID:20683963. Direct evidence on the gene; the abstract does not say whether the ER assays used endogenous or transfected FGFR4.
• The UniProt location "Endoplasmic reticulum" has no evidence tag; it matches the curated IDA.
• Outcome: both rows stay KEEP_AS_NON_CORE (transit pool with direct evidence on the gene, ER batch 1 ABCA4/BACE2 rule); reasons record the check. No NEW GO:0005789: topology does not force a sub-compartment on a transit pool. MARK_AS_OVER_ANNOTATED would apply if the pool were shown to be retention of overexpressed receptor.