FGF19 (human, O95750) curation notes

Identity

• 216 aa secreted protein; UniProt annotates a signal peptide (1..24) and mature chain 25..216; "SUBCELLULAR LOCATION: Secreted." Human ortholog of mouse Fgf15.
• Note: the Falcon deep-research file states FGF19 "lacks a conventional signal peptide" (citing a 2026 review). This conflicts with the UniProt SIGNAL feature 1..24 and should not be used.

Core biology (with provenance)

• Endocrine FGF19 subfamily: reduced heparin-binding affinity confers endocrine mode of action; requires Klotho/betaKlotho
  PMID:17339340
• Receptor: high-affinity, heparin-dependent ligand of FGFR4
  PMID:10525310
• beta-Klotho (KLB) co-receptor is required for FGF19 binding to FGFR4 and signaling
  PMID:17627937
  PMID:17623664
• FGF19 can also signal via KLB-FGFR1c/2c/3c (unlike FGF21, it also signals efficiently through FGFR4)
  PMID:17623664
  PMID:18187602
• Binds both alpha- and beta-Klotho in vitro; C-terminal tail determines Klotho recognition
  PMID:18829467
• Bile acid feedback: FXR induces FGF19; FGF19 represses CYP7A1 in human hepatocytes and mouse liver
  PMID:12815072
  PMID:19085950
  Mouse ortholog: PMID:16213224
• Downstream kinase: ERK1/2 is well supported; JNK is contested.
• Holt 2003: JNK activity increased PMID:12815072
• Song 2009: PMID:19085950 and PMID:19085950
• Hepatic glycogen/protein synthesis (insulin-independent, via Ras-ERK-p90RSK)
  PMID:21436455
  PMID:21436455
• Adipocyte glucose uptake is pharmacological; physiological relevance questioned by the authors
  PMID:17623664

Annotation decisions (summary)

• Core MF: GO:0005104 fibroblast growth factor receptor binding (as in FGFR signaling module).
• Core BP: GO:0008543 FGFR signaling pathway; GO:0070858 negative regulation of bile acid biosynthetic process.
• NEW: GO:0045725 positive regulation of glycogen biosynthetic process (Kir 2011). Comparator check: INS carries GO:0045725 (IDA, PMID:17925406), i.e. hormones that trigger the signalling that raises glycogen synthesis carry this regulation term; the hormone does the signalling work (it is the ligand that activates the receptor), unlike a substrate.
• Hormone activity (GO:0005179): not carried by FGF19, FGF21 or FGF23 in QuickGO (checked 2026-09-30), so not proposed; raised as a question.
• REMOVE: cytoplasm IBA (secreted protein; family node includes intracellular FGFs), response to ethanol IEA (rat expression-response transfer).
• MODIFY: protein binding (KLB, KL) -> GO:0005102 signaling receptor binding; negative regulation of gene expression -> GO:0070858.
• GO:0005615 extracellular space is obsolete in the local GO build; used GO:0005576 extracellular region for core location.