FGF19 is an endocrine member of the fibroblast growth factor family (FGF19/FGF21/FGF23 subfamily; human ortholog of mouse FGF15). It is a secreted protein produced mainly by ileal enterocytes after bile acids activate the nuclear receptor FXR, and it circulates via the portal blood to the liver. Its atypical heparin-binding region gives low heparan sulfate affinity, allowing endocrine action, and it relies on the transmembrane co-receptor beta-Klotho (KLB) for high-affinity binding to and activation of FGF receptors, principally FGFR4 in hepatocytes but also KLB-FGFR1c/2c/3c complexes. In hepatocytes, FGF19-KLB-FGFR4 signaling (mainly via FRS2/ERK1/2, with contested JNK involvement) represses CYP7A1, the rate-limiting enzyme of bile acid synthesis, forming a gut-liver negative feedback loop; it also promotes gallbladder filling and stimulates insulin-independent hepatic protein and glycogen synthesis. Pharmacological FGF19 has additional effects on adipocyte glucose uptake and energy balance, and sustained FGF19-FGFR4 signaling is mitogenic in liver.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001934 positive regulation of protein phosphorylation | IDA PMID:17627937 Liver-specific activities of FGF19 require Klotho beta. | KEEP AS NON CORE | Summary: FGF19 stimulation of KLB/FGFR4-expressing cells induces receptor, FRS2 and ERK phosphorylation. Reason: Correct but very general readout of FGFR activation (abstract-only reference; curator saw full text). The informative downstream events are already captured by positive regulation of ERK1 and ERK2 cascade and FGFR signaling pathway, so this is retained as a non-core, general annotation rather than removed. Supporting Evidence: PMID:17627937 KLB is required for FGF19 binding to FGFR4, intracellular signaling, and downstream modulation of gene expression. |
| GO:0005104 fibroblast growth factor receptor binding | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT places FGF receptor binding at the FGF ligand family node PTN000160075; FGF19 is itself among the experimental seeds. Reason: FGF19 is a bona fide FGFR ligand (FGFR4 with KLB, and KLB-FGFR1c/2c/3c). The IBA correctly reflects the ancestral ligand function of the family, and the target appearing in its own WITH/FROM list reflects its own experimental grounding. Supporting Evidence: PMID:10525310 FGF-19 is a high affinity, heparin dependent ligand for FGFR4 and is the first member of the FGF family to show exclusive binding to FGFR4. PMID:17623664 Both FGF19 and FGF21 can signal through FGFR1-3 bound by betaKlotho and increase glucose uptake in adipocytes expressing FGFR1. |
| GO:0005104 fibroblast growth factor receptor binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro FGF15/19/21 family mapping to FGF receptor binding. Reason: Consistent with direct binding and signaling data for FGF19 via FGFR4 and KLB-FGFR complexes. Supporting Evidence: PMID:10525310 FGF-19 is a high affinity, heparin dependent ligand for FGFR4 and is the first member of the FGF family to show exclusive binding to FGFR4. |
| GO:0005104 fibroblast growth factor receptor binding | IPI PMID:10525310 FGF-19, a novel fibroblast growth factor with unique specifi... | ACCEPT | Summary: Xie et al. 1999 showed FGF19 is a high-affinity, heparin-dependent ligand binding exclusively to FGFR4 (P22455) among FGFRs tested. Reason: Direct binding evidence for the core molecular function. Later work showed KLB is required for high-affinity binding in cells and that KLB also enables binding/signaling through FGFR1c-3c, but FGFR4 binding is the physiological hepatic interaction. Supporting Evidence: PMID:10525310 FGF-19 is a high affinity, heparin dependent ligand for FGFR4 and is the first member of the FGF family to show exclusive binding to FGFR4. |
| GO:0005104 fibroblast growth factor receptor binding | IPI PMID:17627937 Liver-specific activities of FGF19 require Klotho beta. | ACCEPT | Summary: Lin et al. 2007 showed KLB is required for FGF19 binding to FGFR4 (P22455) and for downstream signaling and CYP7A1 repression. Reason: Direct evidence of FGF19-FGFR4 binding in the context of the KLB co-receptor; this is the core ligand activity modelled in the FGFR signaling module. Supporting Evidence: PMID:17627937 KLB is required for FGF19 binding to FGFR4, intracellular signaling, and downstream modulation of gene expression. |
| GO:0005515 protein binding | IPI PMID:18829467 C-terminal tail of FGF19 determines its specificity toward K... | MODIFY | Summary: Wu et al. 2008 report direct binding of FGF19 to beta-Klotho (KLB, Q86Z14), mediated by the FGF19 C-terminal tail. Reason: "Protein binding" is uninformative. The partner is a Klotho-family single-pass transmembrane co-receptor of FGFRs, so the more informative MF is signaling receptor binding. KLB is the physiological FGF19 co-receptor in liver. Proposed replacements: signaling receptor binding Supporting Evidence: PMID:18829467 We previously showed that FGF19 can bind to both alpha and betaKlotho PMID:18829467 C-terminal tail of FGF19 as a region necessary for its recognition of Klotho family proteins |
| GO:0005515 protein binding | IPI PMID:18829467 C-terminal tail of FGF19 determines its specificity toward K... | MODIFY | Summary: Wu et al. 2008 report direct binding of FGF19 to alpha-Klotho (KL, Q9UEF7), mediated by the FGF19 C-terminal tail. Reason: "Protein binding" is uninformative. The partner is a Klotho-family single-pass transmembrane co-receptor of FGFRs, so the more informative MF is signaling receptor binding. Binding to alpha-Klotho was shown in vitro; FGF19 physiological signaling is KLB-dependent, but the Klotho chimera signaling assays in this paper support a receptor-complex interaction. Proposed replacements: signaling receptor binding Supporting Evidence: PMID:18829467 We previously showed that FGF19 can bind to both alpha and betaKlotho PMID:18829467 C-terminal tail of FGF19 as a region necessary for its recognition of Klotho family proteins |
| GO:0005576 extracellular region | IBA GO_REF:0000033 | ACCEPT | Summary: FGF family IBA for extracellular activity. Reason: FGF19 is a secreted endocrine hormone that acts extracellularly on cell-surface KLB-FGFR complexes. Supporting Evidence: PMID:17339340 This reduces the heparin-binding affinity of these ligands and confers endocrine function. |
| GO:0005576 extracellular region | IEA GO_REF:0000120 | ACCEPT | Summary: Combined automated annotation (InterPro + UniProt subcellular location "Secreted"). Reason: FGF19 has a signal peptide and is secreted from ileal enterocytes into the portal circulation. Supporting Evidence: PMID:17339340 This reduces the heparin-binding affinity of these ligands and confers endocrine function. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-109699 | ACCEPT | Summary: Reactome TAS (Reactome:R-HSA-109699) placing FGF19 extracellularly as a ligand in FGFR4 signaling reactions. Reason: Reactome places FGF19 in the extracellular compartment as the ligand for FGFR4/KLB complex reactions. FGF19 is a secreted endocrine hormone (signal peptide 1..24; UniProt "Secreted"), so extracellular region is correct, if general. Accepted as the location of the active ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-1307955 | ACCEPT | Summary: Reactome TAS (Reactome:R-HSA-1307955) placing FGF19 extracellularly as a ligand in FGFR4 signaling reactions. Reason: Reactome places FGF19 in the extracellular compartment as the ligand for FGFR4/KLB complex reactions. FGF19 is a secreted endocrine hormone (signal peptide 1..24; UniProt "Secreted"), so extracellular region is correct, if general. Accepted as the location of the active ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-1307963 | ACCEPT | Summary: Reactome TAS (Reactome:R-HSA-1307963) placing FGF19 extracellularly as a ligand in FGFR4 signaling reactions. Reason: Reactome places FGF19 in the extracellular compartment as the ligand for FGFR4/KLB complex reactions. FGF19 is a secreted endocrine hormone (signal peptide 1..24; UniProt "Secreted"), so extracellular region is correct, if general. Accepted as the location of the active ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-190265 | ACCEPT | Summary: Reactome TAS (Reactome:R-HSA-190265) placing FGF19 extracellularly as a ligand in FGFR4 signaling reactions. Reason: Reactome places FGF19 in the extracellular compartment as the ligand for FGFR4/KLB complex reactions. FGF19 is a secreted endocrine hormone (signal peptide 1..24; UniProt "Secreted"), so extracellular region is correct, if general. Accepted as the location of the active ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-190326 | ACCEPT | Summary: Reactome TAS (Reactome:R-HSA-190326) placing FGF19 extracellularly as a ligand in FGFR4 signaling reactions. Reason: Reactome places FGF19 in the extracellular compartment as the ligand for FGFR4/KLB complex reactions. FGF19 is a secreted endocrine hormone (signal peptide 1..24; UniProt "Secreted"), so extracellular region is correct, if general. Accepted as the location of the active ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-2316434 | ACCEPT | Summary: Reactome TAS (Reactome:R-HSA-2316434) placing FGF19 extracellularly as a ligand in FGFR4 signaling reactions. Reason: Reactome places FGF19 in the extracellular compartment as the ligand for FGFR4/KLB complex reactions. FGF19 is a secreted endocrine hormone (signal peptide 1..24; UniProt "Secreted"), so extracellular region is correct, if general. Accepted as the location of the active ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-2400009 | ACCEPT | Summary: Reactome TAS (Reactome:R-HSA-2400009) placing FGF19 extracellularly as a ligand in FGFR4 signaling reactions. Reason: Reactome places FGF19 in the extracellular compartment as the ligand for FGFR4/KLB complex reactions. FGF19 is a secreted endocrine hormone (signal peptide 1..24; UniProt "Secreted"), so extracellular region is correct, if general. Accepted as the location of the active ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654151 | ACCEPT | Summary: Reactome TAS (Reactome:R-HSA-5654151) placing FGF19 extracellularly as a ligand in FGFR4 signaling reactions. Reason: Reactome places FGF19 in the extracellular compartment as the ligand for FGFR4/KLB complex reactions. FGF19 is a secreted endocrine hormone (signal peptide 1..24; UniProt "Secreted"), so extracellular region is correct, if general. Accepted as the location of the active ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654163 | ACCEPT | Summary: Reactome TAS (Reactome:R-HSA-5654163) placing FGF19 extracellularly as a ligand in FGFR4 signaling reactions. Reason: Reactome places FGF19 in the extracellular compartment as the ligand for FGFR4/KLB complex reactions. FGF19 is a secreted endocrine hormone (signal peptide 1..24; UniProt "Secreted"), so extracellular region is correct, if general. Accepted as the location of the active ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654169 | ACCEPT | Summary: Reactome TAS (Reactome:R-HSA-5654169) placing FGF19 extracellularly as a ligand in FGFR4 signaling reactions. Reason: Reactome places FGF19 in the extracellular compartment as the ligand for FGFR4/KLB complex reactions. FGF19 is a secreted endocrine hormone (signal peptide 1..24; UniProt "Secreted"), so extracellular region is correct, if general. Accepted as the location of the active ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654418 | ACCEPT | Summary: Reactome TAS (Reactome:R-HSA-5654418) placing FGF19 extracellularly as a ligand in FGFR4 signaling reactions. Reason: Reactome places FGF19 in the extracellular compartment as the ligand for FGFR4/KLB complex reactions. FGF19 is a secreted endocrine hormone (signal peptide 1..24; UniProt "Secreted"), so extracellular region is correct, if general. Accepted as the location of the active ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654422 | ACCEPT | Summary: Reactome TAS (Reactome:R-HSA-5654422) placing FGF19 extracellularly as a ligand in FGFR4 signaling reactions. Reason: Reactome places FGF19 in the extracellular compartment as the ligand for FGFR4/KLB complex reactions. FGF19 is a secreted endocrine hormone (signal peptide 1..24; UniProt "Secreted"), so extracellular region is correct, if general. Accepted as the location of the active ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654423 | ACCEPT | Summary: Reactome TAS (Reactome:R-HSA-5654423) placing FGF19 extracellularly as a ligand in FGFR4 signaling reactions. Reason: Reactome places FGF19 in the extracellular compartment as the ligand for FGFR4/KLB complex reactions. FGF19 is a secreted endocrine hormone (signal peptide 1..24; UniProt "Secreted"), so extracellular region is correct, if general. Accepted as the location of the active ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654425 | ACCEPT | Summary: Reactome TAS (Reactome:R-HSA-5654425) placing FGF19 extracellularly as a ligand in FGFR4 signaling reactions. Reason: Reactome places FGF19 in the extracellular compartment as the ligand for FGFR4/KLB complex reactions. FGF19 is a secreted endocrine hormone (signal peptide 1..24; UniProt "Secreted"), so extracellular region is correct, if general. Accepted as the location of the active ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654426 | ACCEPT | Summary: Reactome TAS (Reactome:R-HSA-5654426) placing FGF19 extracellularly as a ligand in FGFR4 signaling reactions. Reason: Reactome places FGF19 in the extracellular compartment as the ligand for FGFR4/KLB complex reactions. FGF19 is a secreted endocrine hormone (signal peptide 1..24; UniProt "Secreted"), so extracellular region is correct, if general. Accepted as the location of the active ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654428 | ACCEPT | Summary: Reactome TAS (Reactome:R-HSA-5654428) placing FGF19 extracellularly as a ligand in FGFR4 signaling reactions. Reason: Reactome places FGF19 in the extracellular compartment as the ligand for FGFR4/KLB complex reactions. FGF19 is a secreted endocrine hormone (signal peptide 1..24; UniProt "Secreted"), so extracellular region is correct, if general. Accepted as the location of the active ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654566 | ACCEPT | Summary: Reactome TAS (Reactome:R-HSA-5654566) placing FGF19 extracellularly as a ligand in FGFR4 signaling reactions. Reason: Reactome places FGF19 in the extracellular compartment as the ligand for FGFR4/KLB complex reactions. FGF19 is a secreted endocrine hormone (signal peptide 1..24; UniProt "Secreted"), so extracellular region is correct, if general. Accepted as the location of the active ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654651 | ACCEPT | Summary: Reactome TAS (Reactome:R-HSA-5654651) placing FGF19 extracellularly as a ligand in FGFR4 signaling reactions. Reason: Reactome places FGF19 in the extracellular compartment as the ligand for FGFR4/KLB complex reactions. FGF19 is a secreted endocrine hormone (signal peptide 1..24; UniProt "Secreted"), so extracellular region is correct, if general. Accepted as the location of the active ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654653 | ACCEPT | Summary: Reactome TAS (Reactome:R-HSA-5654653) placing FGF19 extracellularly as a ligand in FGFR4 signaling reactions. Reason: Reactome places FGF19 in the extracellular compartment as the ligand for FGFR4/KLB complex reactions. FGF19 is a secreted endocrine hormone (signal peptide 1..24; UniProt "Secreted"), so extracellular region is correct, if general. Accepted as the location of the active ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654655 | ACCEPT | Summary: Reactome TAS (Reactome:R-HSA-5654655) placing FGF19 extracellularly as a ligand in FGFR4 signaling reactions. Reason: Reactome places FGF19 in the extracellular compartment as the ligand for FGFR4/KLB complex reactions. FGF19 is a secreted endocrine hormone (signal peptide 1..24; UniProt "Secreted"), so extracellular region is correct, if general. Accepted as the location of the active ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654658 | ACCEPT | Summary: Reactome TAS (Reactome:R-HSA-5654658) placing FGF19 extracellularly as a ligand in FGFR4 signaling reactions. Reason: Reactome places FGF19 in the extracellular compartment as the ligand for FGFR4/KLB complex reactions. FGF19 is a secreted endocrine hormone (signal peptide 1..24; UniProt "Secreted"), so extracellular region is correct, if general. Accepted as the location of the active ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654659 | ACCEPT | Summary: Reactome TAS (Reactome:R-HSA-5654659) placing FGF19 extracellularly as a ligand in FGFR4 signaling reactions. Reason: Reactome places FGF19 in the extracellular compartment as the ligand for FGFR4/KLB complex reactions. FGF19 is a secreted endocrine hormone (signal peptide 1..24; UniProt "Secreted"), so extracellular region is correct, if general. Accepted as the location of the active ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654662 | ACCEPT | Summary: Reactome TAS (Reactome:R-HSA-5654662) placing FGF19 extracellularly as a ligand in FGFR4 signaling reactions. Reason: Reactome places FGF19 in the extracellular compartment as the ligand for FGFR4/KLB complex reactions. FGF19 is a secreted endocrine hormone (signal peptide 1..24; UniProt "Secreted"), so extracellular region is correct, if general. Accepted as the location of the active ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654663 | ACCEPT | Summary: Reactome TAS (Reactome:R-HSA-5654663) placing FGF19 extracellularly as a ligand in FGFR4 signaling reactions. Reason: Reactome places FGF19 in the extracellular compartment as the ligand for FGFR4/KLB complex reactions. FGF19 is a secreted endocrine hormone (signal peptide 1..24; UniProt "Secreted"), so extracellular region is correct, if general. Accepted as the location of the active ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654664 | ACCEPT | Summary: Reactome TAS (Reactome:R-HSA-5654664) placing FGF19 extracellularly as a ligand in FGFR4 signaling reactions. Reason: Reactome places FGF19 in the extracellular compartment as the ligand for FGFR4/KLB complex reactions. FGF19 is a secreted endocrine hormone (signal peptide 1..24; UniProt "Secreted"), so extracellular region is correct, if general. Accepted as the location of the active ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654667 | ACCEPT | Summary: Reactome TAS (Reactome:R-HSA-5654667) placing FGF19 extracellularly as a ligand in FGFR4 signaling reactions. Reason: Reactome places FGF19 in the extracellular compartment as the ligand for FGFR4/KLB complex reactions. FGF19 is a secreted endocrine hormone (signal peptide 1..24; UniProt "Secreted"), so extracellular region is correct, if general. Accepted as the location of the active ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654669 | ACCEPT | Summary: Reactome TAS (Reactome:R-HSA-5654669) placing FGF19 extracellularly as a ligand in FGFR4 signaling reactions. Reason: Reactome places FGF19 in the extracellular compartment as the ligand for FGFR4/KLB complex reactions. FGF19 is a secreted endocrine hormone (signal peptide 1..24; UniProt "Secreted"), so extracellular region is correct, if general. Accepted as the location of the active ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654684 | ACCEPT | Summary: Reactome TAS (Reactome:R-HSA-5654684) placing FGF19 extracellularly as a ligand in FGFR4 signaling reactions. Reason: Reactome places FGF19 in the extracellular compartment as the ligand for FGFR4/KLB complex reactions. FGF19 is a secreted endocrine hormone (signal peptide 1..24; UniProt "Secreted"), so extracellular region is correct, if general. Accepted as the location of the active ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654714 | ACCEPT | Summary: Reactome TAS (Reactome:R-HSA-5654714) placing FGF19 extracellularly as a ligand in FGFR4 signaling reactions. Reason: Reactome places FGF19 in the extracellular compartment as the ligand for FGFR4/KLB complex reactions. FGF19 is a secreted endocrine hormone (signal peptide 1..24; UniProt "Secreted"), so extracellular region is correct, if general. Accepted as the location of the active ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654717 | ACCEPT | Summary: Reactome TAS (Reactome:R-HSA-5654717) placing FGF19 extracellularly as a ligand in FGFR4 signaling reactions. Reason: Reactome places FGF19 in the extracellular compartment as the ligand for FGFR4/KLB complex reactions. FGF19 is a secreted endocrine hormone (signal peptide 1..24; UniProt "Secreted"), so extracellular region is correct, if general. Accepted as the location of the active ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654734 | ACCEPT | Summary: Reactome TAS (Reactome:R-HSA-5654734) placing FGF19 extracellularly as a ligand in FGFR4 signaling reactions. Reason: Reactome places FGF19 in the extracellular compartment as the ligand for FGFR4/KLB complex reactions. FGF19 is a secreted endocrine hormone (signal peptide 1..24; UniProt "Secreted"), so extracellular region is correct, if general. Accepted as the location of the active ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5672965 | ACCEPT | Summary: Reactome TAS (Reactome:R-HSA-5672965) placing FGF19 extracellularly as a ligand in FGFR4 signaling reactions. Reason: Reactome places FGF19 in the extracellular compartment as the ligand for FGFR4/KLB complex reactions. FGF19 is a secreted endocrine hormone (signal peptide 1..24; UniProt "Secreted"), so extracellular region is correct, if general. Accepted as the location of the active ligand. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | REMOVE | Summary: IBA is_active_in cytoplasm propagated from the FGF family node; donors include intracellular/nuclear-acting FGFs. Reason: FGF19 is a secreted endocrine FGF with a cleavable signal peptide (UniProt SIGNAL 1..24, "Secreted") whose activity is exerted extracellularly on KLB-FGFR complexes. There is no evidence of an FGF19 activity in the cytoplasm; the cytoplasmic activity of FGF1/FGF2 isoforms and intracellular FGFs has been over-propagated to this divergent endocrine subfamily member. Propagation Review Root cause: PROPAGATION BAD Failure modes: COMPARTMENT OR COMPLEX MISMATCH FUNCTIONAL DIVERGENCE Supporting Evidence: PMID:17339340 This reduces the heparin-binding affinity of these ligands and confers endocrine function. |
| GO:0007399 nervous system development | TAS PMID:9931477 Structure and expression of a novel human FGF, FGF-19, expre... | MARK AS OVER ANNOTATED | Summary: TAS from the cloning paper (Nishimura 1999) reporting FGF19 expression in fetal brain. Reason: The reference is a cloning/expression report (abstract not available); expression in fetal brain does not demonstrate a role in nervous system development for human FGF19. The established human physiology is endocrine metabolic signaling. Retained at most as a family-level possibility (see neurogenesis IBA). |
| GO:0008083 growth factor activity | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA growth factor activity from FGF family membership. Reason: FGF19 is a receptor ligand that can be mitogenic (full stimulation of BaF3 proliferation via KLB-FGFR complexes; hepatocyte proliferation), so growth factor activity is not wrong. However its physiological role is as an endocrine metabolic hormone; the core ligand activity is better captured by fibroblast growth factor receptor binding. Supporting Evidence: PMID:18187602 By contrast, these cells were stimulated fully by FGF19, which induced maximal DNA synthesis at levels comparable to FGF1 in all four transfectants examined. |
| GO:0008083 growth factor activity | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: IEA growth factor activity from FGF family membership. Reason: FGF19 is a receptor ligand that can be mitogenic (full stimulation of BaF3 proliferation via KLB-FGFR complexes; hepatocyte proliferation), so growth factor activity is not wrong. However its physiological role is as an endocrine metabolic hormone; the core ligand activity is better captured by fibroblast growth factor receptor binding. Supporting Evidence: PMID:18187602 By contrast, these cells were stimulated fully by FGF19, which induced maximal DNA synthesis at levels comparable to FGF1 in all four transfectants examined. |
| GO:0008284 positive regulation of cell population proliferation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Family-level IBA for positive regulation of cell proliferation. Reason: Mitogenic FGFR signaling is an ancestral FGF property and FGF19 retains it (BaF3 assays; hepatocyte proliferation), but proliferation is not the physiological core role of FGF19. Supporting Evidence: PMID:18187602 By contrast, these cells were stimulated fully by FGF19, which induced maximal DNA synthesis at levels comparable to FGF1 in all four transfectants examined. |
| GO:0008284 positive regulation of cell population proliferation | IGI PMID:18187602 betaKlotho is required for fibroblast growth factor (FGF) 21... | KEEP AS NON CORE | Summary: IGI (MGI) from Suzuki et al. 2008: FGF19 stimulated DNA synthesis in BaF3 cells engineered to express betaKlotho plus a mouse FGFR (UniProtKB:P16092). Reason: The BaF3 proliferation assay is a reconstituted receptor-activation readout, not a physiological proliferative role. The acts_upstream_of_or_within qualifier is appropriate; retained as non-core. Supporting Evidence: PMID:18187602 By contrast, these cells were stimulated fully by FGF19, which induced maximal DNA synthesis at levels comparable to FGF1 in all four transfectants examined. |
| GO:0008284 positive regulation of cell population proliferation | IGI PMID:18187602 betaKlotho is required for fibroblast growth factor (FGF) 21... | KEEP AS NON CORE | Summary: IGI (MGI) from Suzuki et al. 2008: FGF19 stimulated DNA synthesis in BaF3 cells engineered to express betaKlotho plus a mouse FGFR (UniProtKB:P21803). Reason: The BaF3 proliferation assay is a reconstituted receptor-activation readout, not a physiological proliferative role. The acts_upstream_of_or_within qualifier is appropriate; retained as non-core. Supporting Evidence: PMID:18187602 By contrast, these cells were stimulated fully by FGF19, which induced maximal DNA synthesis at levels comparable to FGF1 in all four transfectants examined. |
| GO:0008284 positive regulation of cell population proliferation | IGI PMID:18187602 betaKlotho is required for fibroblast growth factor (FGF) 21... | KEEP AS NON CORE | Summary: IGI (MGI) from Suzuki et al. 2008: FGF19 stimulated DNA synthesis in BaF3 cells engineered to express betaKlotho plus a mouse FGFR (UniProtKB:Q03142). Reason: The BaF3 proliferation assay is a reconstituted receptor-activation readout, not a physiological proliferative role. The acts_upstream_of_or_within qualifier is appropriate; retained as non-core. Supporting Evidence: PMID:18187602 By contrast, these cells were stimulated fully by FGF19, which induced maximal DNA synthesis at levels comparable to FGF1 in all four transfectants examined. |
| GO:0008284 positive regulation of cell population proliferation | IGI PMID:18187602 betaKlotho is required for fibroblast growth factor (FGF) 21... | KEEP AS NON CORE | Summary: IGI (MGI) from Suzuki et al. 2008: FGF19 stimulated DNA synthesis in BaF3 cells engineered to express betaKlotho plus a mouse FGFR (UniProtKB:Q61851). Reason: The BaF3 proliferation assay is a reconstituted receptor-activation readout, not a physiological proliferative role. The acts_upstream_of_or_within qualifier is appropriate; retained as non-core. Supporting Evidence: PMID:18187602 By contrast, these cells were stimulated fully by FGF19, which induced maximal DNA synthesis at levels comparable to FGF1 in all four transfectants examined. |
| GO:0008543 fibroblast growth factor receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT family-level annotation to FGFR signaling pathway. Reason: FGF19 is an FGFR ligand that initiates FGFR signaling in KLB-expressing cells. Supporting Evidence: PMID:17623664 Both FGF19 and FGF21 can signal through FGFR1-3 bound by betaKlotho and increase glucose uptake in adipocytes expressing FGFR1. |
| GO:0008543 fibroblast growth factor receptor signaling pathway | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro FGF15/19/21 mapping to FGFR signaling pathway. Reason: Consistent with experimental data. Supporting Evidence: PMID:17623664 Both FGF19 and FGF21 can signal through FGFR1-3 bound by betaKlotho and increase glucose uptake in adipocytes expressing FGFR1. |
| GO:0008543 fibroblast growth factor receptor signaling pathway | IGI PMID:18187602 betaKlotho is required for fibroblast growth factor (FGF) 21... | ACCEPT | Summary: IGI (MGI) from Suzuki et al. 2008: FGF19 activated signaling in BaF3 cells coexpressing betaKlotho and FGFR (UniProtKB:P16092). Reason: Direct demonstration that FGF19 activates FGFR signaling through each receptor in the presence of betaKlotho. Supporting Evidence: PMID:18187602 By contrast, these cells were stimulated fully by FGF19, which induced maximal DNA synthesis at levels comparable to FGF1 in all four transfectants examined. |
| GO:0008543 fibroblast growth factor receptor signaling pathway | IGI PMID:18187602 betaKlotho is required for fibroblast growth factor (FGF) 21... | ACCEPT | Summary: IGI (MGI) from Suzuki et al. 2008: FGF19 activated signaling in BaF3 cells coexpressing betaKlotho and FGFR (UniProtKB:P21803). Reason: Direct demonstration that FGF19 activates FGFR signaling through each receptor in the presence of betaKlotho. Supporting Evidence: PMID:18187602 By contrast, these cells were stimulated fully by FGF19, which induced maximal DNA synthesis at levels comparable to FGF1 in all four transfectants examined. |
| GO:0008543 fibroblast growth factor receptor signaling pathway | IGI PMID:18187602 betaKlotho is required for fibroblast growth factor (FGF) 21... | ACCEPT | Summary: IGI (MGI) from Suzuki et al. 2008: FGF19 activated signaling in BaF3 cells coexpressing betaKlotho and FGFR (UniProtKB:Q03142). Reason: Direct demonstration that FGF19 activates FGFR signaling through each receptor in the presence of betaKlotho. Supporting Evidence: PMID:18187602 By contrast, these cells were stimulated fully by FGF19, which induced maximal DNA synthesis at levels comparable to FGF1 in all four transfectants examined. |
| GO:0008543 fibroblast growth factor receptor signaling pathway | IGI PMID:18187602 betaKlotho is required for fibroblast growth factor (FGF) 21... | ACCEPT | Summary: IGI (MGI) from Suzuki et al. 2008: FGF19 activated signaling in BaF3 cells coexpressing betaKlotho and FGFR (UniProtKB:Q61851). Reason: Direct demonstration that FGF19 activates FGFR signaling through each receptor in the presence of betaKlotho. Supporting Evidence: PMID:18187602 By contrast, these cells were stimulated fully by FGF19, which induced maximal DNA synthesis at levels comparable to FGF1 in all four transfectants examined. |
| GO:0008543 fibroblast growth factor receptor signaling pathway | IPI PMID:10525310 FGF-19, a novel fibroblast growth factor with unique specifi... | ACCEPT | Summary: IPI (MGI) from Xie et al. 1999: FGF19 binds FGFR4 (P22455). Reason: FGF19 binding to FGFR4 initiates FGFR signaling; acts_upstream_of_or_within is appropriate for the binding evidence and the core process is well established by later signaling studies. Supporting Evidence: PMID:10525310 FGF-19 is a high affinity, heparin dependent ligand for FGFR4 and is the first member of the FGF family to show exclusive binding to FGFR4. |
| GO:0010629 negative regulation of gene expression | IDA PMID:19085950 Bile acids activate fibroblast growth factor 19 signaling in... | MODIFY | Summary: Song et al. 2009: FGF19 represses CYP7A1 mRNA in primary human hepatocytes. Reason: Correct but very general. The gene whose expression is repressed is CYP7A1, the rate-limiting bile acid synthetic enzyme, and the biologically meaningful process is negative regulation of bile acid biosynthetic process (already annotated by IDA from PMID:12815072). Proposed replacements: negative regulation of bile acid biosynthetic process Supporting Evidence: PMID:19085950 FGF19 strongly and rapidly repressed CYP7A1 but not small heterodimer partner (SHP) mRNA levels. |
| GO:0022008 neurogenesis | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Family-level IBA for neurogenesis. Reason: Neurodevelopmental roles are documented for FGF family members and for FGF19 orthologs in zebrafish/mouse brain development, so the phylogenetic placement is plausible, but there is no direct evidence for human FGF19 and it is not part of its core endocrine function. |
| GO:0030334 regulation of cell migration | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Family-level IBA for regulation of cell migration. Reason: Regulation of migration is a general FGF family property; no FGF19-specific physiological evidence was found in the reviewed literature. Retained as non-core family-level inference rather than removed, as there is no evidence of loss. |
| GO:0043410 positive regulation of MAPK cascade | IBA GO_REF:0000033 | ACCEPT | Summary: Family-level IBA for positive regulation of MAPK cascade. Reason: Supported by direct FGF19 evidence: FGF19 stimulates ERK1/2 phosphorylation in human hepatocytes and in liver in vivo. Supporting Evidence: PMID:19085950 FGF19 (40 ng/ml) time-dependently stimulated phosphorylation of ERK1/2 in primary human hepatocytes PMID:17623664 FGF19 activated FGF signaling robustly in liver and weakly in white adipose tissue as evidenced by induction of ERK phosphorylation |
| GO:0045471 response to ethanol | IEA GO_REF:0000107 | REMOVE | Summary: Ensembl Compara transfer of a rat annotation (response to ethanol) to human FGF19. Reason: The source is a rat expression-response observation; "response to ethanol" does not describe an activity of FGF19 and there is no evidence that human FGF19 participates in an ethanol response. Electronic transfer of an expression-change term is over-propagation. |
| GO:0046326 positive regulation of D-glucose import across plasma membrane | IDA PMID:17623664 Tissue-specific expression of betaKlotho and fibroblast grow... | KEEP AS NON CORE | Summary: Kurosu et al. 2007: FGF19 increased glucose uptake in 3T3-L1 adipocytes via betaKlotho-FGFR1. Reason: Experimentally shown (pharmacological dosing in a mouse adipocyte line), but the authors note that the physiological contribution of FGF15/19 to adipocyte function may be minimal. Kept as non-core. Supporting Evidence: PMID:17623664 Indeed, FGF19 significantly increased glucose uptake within 18 h, which was comparable with that induced by FGF21 PMID:17623664 contribution of FGF15/19 to the regulation of adipocyte function could be minimal under physiological conditions |
| GO:0046326 positive regulation of D-glucose import across plasma membrane | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA machine-learning prediction of positive regulation of glucose import. Reason: Consistent with the adipocyte glucose uptake data for FGF19 (PMID:17623664), but pharmacological and non-core. Supporting Evidence: PMID:17623664 Indeed, FGF19 significantly increased glucose uptake within 18 h, which was comparable with that induced by FGF21 |
| GO:0046330 positive regulation of JNK cascade | IDA PMID:12815072 Definition of a novel growth factor-dependent signal cascade... | KEEP AS NON CORE | Summary: Holt et al. 2003: FGF19 increased JNK activity (c-Jun phosphorylation) in primary human hepatocytes, and a JNK inhibitor partially relieved CYP7A1 suppression. Reason: The IDA is valid for the reported experiment, but a later study in primary human hepatocytes did not detect JNK activation by FGF19 and implicated ERK1/2 as the main mediator. Retained as a non-core, contested downstream output. Supporting Evidence: PMID:12815072 Thus, FGF-19 treatment of primary human hepatocytes is able to activate the JNK pathway. PMID:19085950 Surprisingly, FGF19 did not activate JNK in this assay. |
| GO:0070374 positive regulation of ERK1 and ERK2 cascade | IDA PMID:17623664 Tissue-specific expression of betaKlotho and fibroblast grow... | ACCEPT | Summary: Kurosu et al. 2007: FGF19 induced FRS2alpha and ERK1/2 phosphorylation in betaKlotho-expressing cells and in liver in vivo. Reason: Robust, reproducible downstream output of FGF19-KLB-FGFR signaling that mediates its metabolic effects. Supporting Evidence: PMID:17623664 FGF19 activated FGF signaling robustly in liver and weakly in white adipose tissue as evidenced by induction of ERK phosphorylation |
| GO:0070374 positive regulation of ERK1 and ERK2 cascade | IDA PMID:19085950 Bile acids activate fibroblast growth factor 19 signaling in... | ACCEPT | Summary: Song et al. 2009: FGF19 stimulated ERK1/2 phosphorylation in primary human hepatocytes; ERK1/2 inhibition blocked FGF19 repression of CYP7A1. Reason: Direct evidence in primary human hepatocytes; ERK1/2 is the main mediator of FGF19 repression of CYP7A1. Supporting Evidence: PMID:19085950 FGF19 (40 ng/ml) time-dependently stimulated phosphorylation of ERK1/2 in primary human hepatocytes |
| GO:0070858 negative regulation of bile acid biosynthetic process | IDA PMID:12815072 Definition of a novel growth factor-dependent signal cascade... | ACCEPT | Summary: Holt et al. 2003: FGF19 suppresses CYP7A1 expression in primary human hepatocytes and mouse liver. Reason: Core physiological function of FGF19: the intestinal FXR-FGF19-hepatic KLB/FGFR4 feedback loop that represses bile acid synthesis, confirmed by multiple groups and by Fgf15-null mice. Supporting Evidence: PMID:12815072 FGF-19 strongly suppresses expression of CYP7A1 in primary cultures of human hepatocytes and mouse liver through a c-Jun N-terminal kinase (JNK)-dependent pathway. PMID:19085950 FGF19 strongly and rapidly repressed CYP7A1 but not small heterodimer partner (SHP) mRNA levels. PMID:17623664 Accordingly, FGF19, but not FGF21, activates FGF signaling in hepatocytes that primarily express FGFR4 and reduces transcription of CYP7A1 that encodes the rate-limiting enzyme for bile acid synthesis. file:human/FGF19/FGF19-deep-research-falcon.md The most well-established primary function of FGF19 is regulation of bile acid synthesis through negative feedback in the enterohepatic circulation |
| GO:0045725 positive regulation of glycogen biosynthetic process | IDA PMID:21436455 FGF19 as a postprandial, insulin-independent activator of he... | NEW | Summary: Kir et al. 2011: human FGF19 stimulated hepatic glycogen synthase activity and glycogen synthesis in mice and rats, independently of insulin/Akt, via Ras-ERK-p90RSK; Fgf15-null mice have reduced postprandial liver glycogen. Reason: FGF19 acts as the hormone ligand that initiates the signaling increasing glycogen synthesis; this is the same relationship by which INS carries GO:0045725 (QuickGO: IDA PMID:17925406). The process term is a regulation term and FGF19 performs the signal-initiating step, so the participation test is satisfied. Not previously annotated in GOA. Supporting Evidence: PMID:21436455 We show that FGF19 stimulates hepatic protein and glycogen synthesis but does not induce lipogenesis. PMID:21436455 Because recombinant mouse FGF15 is unstable and has variable bioactivity, we used human FGF19 for these studies. |
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Download this section (compressed HTML)Q: Should endocrine FGFs (FGF19, FGF21, FGF23) carry hormone activity (GO:0005179) in addition to FGF receptor binding? None currently do in GOA, although all three act as circulating hormones.
Q: Is JNK activation a genuine output of FGF19-KLB-FGFR4 signaling in human hepatocytes, given conflicting results (Holt 2003 vs Song 2009)?
Q: Which FGFR isoform(s) mediate FGF19-induced gallbladder filling, given that it persists in FGFR4-deficient mice?
Q: Does FGF19 act physiologically on adipocytes or the CNS via KLB-FGFR1c, or are these effects restricted to pharmacological concentrations?
Experiment: Treat primary human hepatocytes with FGF19 and selectively inhibit or genetically ablate MEK/ERK versus JNK; quantify CYP7A1 mRNA and phospho-substrate levels to resolve the pathway conflict between the 2003 and 2009 studies.
Hypothesis: ERK1/2 rather than JNK is the necessary mediator of FGF19 repression of CYP7A1 in human hepatocytes.
Experiment: Compare FGF19-induced FGFR/ERK signaling and metabolic readouts across primary hepatocytes, adipocytes and hypothalamic neurons after KLB knockdown/knockout, testing whether responses track KLB expression at physiological versus pharmacological FGF19 concentrations.
Hypothesis: beta-Klotho availability is the tissue-selectivity switch that restricts physiological FGF19 action to KLB-expressing tissues.
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