FGFRL1

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005007 fibroblast growth factor receptor activity	IBA GO_REF:0000033	MODIFY	Summary: FGFRL1 binds FGF ligands through its extracellular Ig-like domains but lacks the intracellular tyrosine kinase domain required for signal transduction. The GO definition of "fibroblast growth factor receptor activity" (GO:0005007) specifies "Combining with a fibroblast growth factor to initiate a change in cell activity," implying signal transduction capability. FGFRL1 cannot transduce signals via autophosphorylation and instead acts as a decoy receptor [PMID:12813049, PMID:35053442]. However, the IBA annotation reflects phylogenetic grouping within the FGFR family, and there is evidence that FGFRL1 can modulate signaling through non-canonical mechanisms such as SPRED1 interaction [PMID:21616146]. Reason: While FGFRL1 is phylogenetically related to FGFRs and binds FGF ligands, it lacks the tyrosine kinase domain and cannot perform canonical receptor signaling [PMID:12813049]. The term "receptor activity" implies signal transduction which FGFRL1 does not perform. A more accurate annotation would be "fibroblast growth factor binding" (GO:0017134), which captures the core FGF-binding function without implying signal transduction. Proposed replacements: fibroblast growth factor binding Supporting Evidence: PMID:12813049 Similar to FGF receptors, the expressed protein interacted specifically with heparin and with FGF2. When overexpressed in MG-63 osteosarcoma cells, the novel receptor had a negative effect on cell proliferation. Taken together our data are consistent with the view that FGFRL1 acts as a decoy receptor for FGF ligands. Reactome:R-HSA-5654511 FGFRL1 lacks the internal kinase domain required for typical downstream FGFR signaling... FGFRL1 has been postulated to act as a decoy receptor that sequesters ligand away from canonical FGF receptors
GO:0005886 plasma membrane	IBA GO_REF:0000033	ACCEPT	Summary: FGFRL1 is a single-pass type I transmembrane protein that localizes to the plasma membrane where it forms constitutive homodimers and mediates cell adhesion. Multiple experimental studies confirm plasma membrane localization [PMID:12813049, PMID:18061161]. UniProt also states "Predominantly localized in the plasma membrane." Reason: This cellular component annotation is strongly supported by multiple experimental studies using GFP fusion proteins [PMID:12813049], FRET [PMID:18061161], and immunostaining. The IBA annotation is consistent with all available evidence. Supporting Evidence: PMID:12813049 When expressed in cultured cells as a fusion protein with green fluorescent protein, FGFRL1 was specifically localized to the plasma membrane where it might interact with FGF ligands. PMID:18061161 FGFRL1 forms constitutive homodimers at cell surfaces.
GO:0017134 fibroblast growth factor binding	IBA GO_REF:0000033	ACCEPT	Summary: FGFRL1 directly binds multiple FGF ligands including FGF2, FGF3, FGF4, FGF8, FGF10, and FGF22 through its extracellular Ig-like domains. Binding was demonstrated by dot blot, cell binding, and SPR assays [PMID:12813049, Reactome:R-HSA-5654511]. This is a core molecular function of FGFRL1. Reason: FGF binding is the primary molecular function of FGFRL1 and is well-established experimentally. The IBA annotation is at the correct level of specificity. Supporting Evidence: PMID:12813049 Similar to FGF receptors, the expressed protein interacted specifically with heparin and with FGF2. Reactome:R-HSA-5654511 FGFRL1 forms constitutive dimers and has been shown to bind to a wide range of FGF ligands, including FGF3,4,8,10, 22 and with lower affinity to FGF2,5,17,18 and 23
GO:0008543 fibroblast growth factor receptor signaling pathway	IEA GO_REF:0000108	MODIFY	Summary: This IEA annotation was logically inferred from the GO:0005007 (FGF receptor activity) annotation. However, FGFRL1 does not participate in canonical FGF receptor signaling because it lacks the intracellular kinase domain [PMID:12813049]. Rather, it negatively regulates the pathway by sequestering FGF ligands away from canonical receptors [PMID:35053442, Reactome:R-HSA-5654511]. Reason: FGFRL1 does not transduce FGF signals. It acts as a decoy receptor that negatively modulates the FGF signaling pathway. The annotation should reflect this regulatory role rather than direct pathway participation. Proposed replacements: negative regulation of fibroblast growth factor receptor signaling pathway Supporting Evidence: PMID:12813049 Taken together our data are consistent with the view that FGFRL1 acts as a decoy receptor for FGF ligands. PMID:35053442 Functional studies indicated that FGFRL1-KD in PC3M cells increases FGFR signaling, whereas FGFRL1 overexpression attenuates it, supporting decoy receptor actions of membrane-localized FGFRL1
GO:0016020 membrane	IEA GO_REF:0000044	MARK AS OVER ANNOTATED	Summary: FGFRL1 is a transmembrane protein that localizes primarily to the plasma membrane and can also be found in Golgi and transport vesicles during trafficking. This broad term is automatically mapped from the UniProt subcellular location annotation. Reason: This is a valid but general cellular component term derived from the UniProt subcellular location entry. More specific terms (plasma membrane, Golgi apparatus) are also annotated. The IEA mapping is technically correct, but it is wholly subsumed by those more specific terms and so conveys nothing that is not already annotated. [2026-08 SL project re-review] Uninformative parent from the UniProt subcellular-location pipeline. The sole source for this annotation is GO_REF:0000044 (UniProtKB-SubCell), and the gene already carries strictly more specific term(s) from independent evidence, namely GO:0005886 plasma membrane (IBA). The term is not false; it is an under-specified location that adds no information over what is already annotated, which is the dominant failure mode of the SL pipeline (see projects/SL.md). Marked over-annotated rather than MODIFY because the more precise term is already present, so there is nothing to replace it with. Supporting Evidence: PMID:12813049 When expressed in cultured cells as a fusion protein with green fluorescent protein, FGFRL1 was specifically localized to the plasma membrane where it might interact with FGF ligands.
GO:0001501 skeletal system development	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: FGFRL1 is preferentially expressed in skeletal tissues including cartilage and bone [PMID:12813049]. Knockout mice show cranial abnormalities including a dome-shaped skull, and FGFRL1 is implicated in craniosynostosis. This annotation is transferred from the mouse ortholog via Ensembl Compara. Reason: Skeletal system development is well-supported by expression data and knockout phenotypes, but it is a downstream developmental consequence of FGFRL1's core molecular functions (FGF binding, cell adhesion, cell-cell fusion) rather than a core function itself. FGFRL1 is expressed in skeletal tissues [PMID:12813049] and knockout mice show cranial defects. Supporting Evidence: PMID:12813049 FGFRL1 was expressed preferentially in skeletal tissues as demonstrated by Northern blotting and in situ hybridization. file:human/FGFRL1/FGFRL1-deep-research.md The most striking phenotypes are absence of kidneys, a malformed diaphragm, and a dome-shaped skull
GO:0003179 heart valve morphogenesis	IEA GO_REF:0000107	UNDECIDED	Summary: This annotation is transferred from the mouse ortholog via Ensembl Compara. While FGFRL1 is expressed in heart tissue, the primary literature on FGFRL1 knockout mice focuses on kidney, diaphragm, and skeletal phenotypes. No specific evidence for heart valve morphogenesis defects was found in the available publications [PMID:22432025, PMID:12813049, PMID:18061161]. Reason: Unable to verify the mouse phenotypic data underlying this ortholog transfer. The available FGFRL1 knockout publications do not describe heart valve morphogenesis defects. The deep research mentions FGFRL1 is expressed in developing heart but is unclear about specific cardiac roles. The original mouse annotation source should be consulted to evaluate this annotation.
GO:0005007 fibroblast growth factor receptor activity	IEA GO_REF:0000120	MODIFY	Summary: This is a combined automated IEA annotation for FGF receptor activity. Same considerations as the IBA annotation above apply: FGFRL1 binds FGFs but lacks the kinase domain required for canonical receptor signaling [PMID:12813049]. Reason: Same reasoning as the IBA receptor activity annotation. FGFRL1 binds FGFs but does not have true receptor signaling activity. Should be annotated as FGF binding instead. Proposed replacements: fibroblast growth factor binding Supporting Evidence: PMID:12813049 Similar to FGF receptors, the expressed protein interacted specifically with heparin and with FGF2. Reactome:R-HSA-5654511 FGFRL1 lacks the internal kinase domain required for typical downstream FGFR signaling
GO:0005886 plasma membrane	IEA GO_REF:0000107	ACCEPT	Summary: Duplicate plasma membrane annotation from Ensembl ortholog transfer. FGFRL1 is correctly localized to the plasma membrane as confirmed by multiple experimental approaches. Reason: Accurate cellular component annotation. Consistent with IBA and IDA annotations for the same term.
GO:0008285 negative regulation of cell population proliferation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: FGFRL1 overexpression reduces cell proliferation in MG-63 osteosarcoma cells [PMID:12813049] and in mesenchymal cells [PMID:35053442], consistent with its role as a decoy receptor that sequesters growth-promoting FGF signals. Reason: This biological process is well-supported experimentally but represents a downstream consequence of FGFRL1's FGF sequestration activity rather than a core evolved function. The anti-proliferative effect is a secondary outcome of its decoy receptor function. Supporting Evidence: PMID:12813049 When overexpressed in MG-63 osteosarcoma cells, the novel receptor had a negative effect on cell proliferation. PMID:35053442 In mesenchymal cells, FGFRL1 inhibits cell proliferation
GO:0017134 fibroblast growth factor binding	IEA GO_REF:0000107	ACCEPT	Summary: Duplicate FGF binding annotation from Ensembl ortholog transfer. FGFRL1 binds multiple FGF ligands through its extracellular domains, a well-established core function. Reason: Accurate molecular function annotation consistent with the IBA annotation and extensive experimental evidence.
GO:0060412 ventricular septum morphogenesis	IEA GO_REF:0000107	UNDECIDED	Summary: This annotation is transferred from the mouse ortholog via Ensembl Compara. The available FGFRL1 literature does not describe ventricular septum defects in knockout mice. The primary phenotypes are kidney agenesis, diaphragm malformation, and cranial defects [PMID:22432025]. Reason: Unable to verify the mouse phenotypic data underlying this ortholog transfer. No specific evidence for ventricular septum morphogenesis involvement was found in the accessible FGFRL1 publications. The original mouse annotation source should be consulted.
GO:0060539 diaphragm development	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: FGFRL1 is essential for diaphragm development. Knockout mice die perinatally because the diaphragm muscle is not strong enough to inflate the lungs [PMID:22432025]. The diaphragm lacks slow-twitch muscle fibers, and this is linked to FGFRL1's fusogenic activity. Reason: Diaphragm development is strongly supported by the lethal phenotype in Fgfrl1 knockout mice. However, it represents a developmental process outcome rather than a core molecular function. FGFRL1's involvement in diaphragm development is likely mediated through its cell-cell fusion and adhesion activities. Supporting Evidence: PMID:22432025 Fgfrl1 knock-out mice die shortly after birth due to malformation of the diaphragm. The mutant diaphragm muscle obviously is not strong enough to inflate the lungs after birth. file:human/FGFRL1/FGFRL1-deep-research.md The most striking phenotypes are absence of kidneys, a malformed diaphragm, and a dome-shaped skull
GO:0042802 identical protein binding	IPI PMID:18061161 The cell surface receptor FGFRL1 forms constitutive dimers t...	ACCEPT	Summary: FGFRL1 forms constitutive homodimers at the cell surface as demonstrated by FRET and co-precipitation experiments [PMID:18061161]. This homodimerization is constitutive (not ligand-dependent) and underlies its cell adhesion function. Reason: This molecular function annotation is directly supported by experimental evidence. FGFRL1 homodimerization is a core property that distinguishes it from canonical FGFRs (which dimerize upon ligand binding). While "identical protein binding" is generally vague, in this case the constitutive homodimerization is a specific and functionally important property. Supporting Evidence: PMID:18061161 Utilizing the FRET (fluorescence resonance energy transfer) technique, we demonstrate that FGFRL1 forms constitutive homodimers at cell surfaces. The formation of homodimers was verified by co-precipitation of differentially tagged FGFRL1 polypeptides from solution.
GO:0005886 plasma membrane	IDA PMID:18061161 The cell surface receptor FGFRL1 forms constitutive dimers t...	ACCEPT	Summary: FGFRL1 localizes to the plasma membrane where it forms homodimers. Demonstrated by FRET at cell surfaces and enrichment at cell-cell contact sites [PMID:18061161]. Reason: Accurate cellular component annotation with strong experimental support from FRET studies at cell surfaces. Supporting Evidence: PMID:18061161 FGFRL1 forms constitutive homodimers at cell surfaces.
GO:0008201 heparin binding	IMP PMID:18061161 The cell surface receptor FGFRL1 forms constitutive dimers t...	ACCEPT	Summary: FGFRL1 binds heparin and heparan sulfate, and this binding is required for its cell adhesion function. Mutation of the putative heparin-binding site reduced heparin affinity and cell-binding activity [PMID:18061161]. The wild-type protein elutes from heparin-Sepharose at ~680 mM NaCl versus ~510 mM for the mutant. Reason: Heparin binding is a core molecular function of FGFRL1 that is essential for its cell adhesion activity. Well-supported by mutational analysis and biochemical experiments. Supporting Evidence: PMID:18061161 Adhesion was mediated by heparan sulfate glycosaminoglycans located at the cell surface. It could specifically be blocked by addition of soluble heparin but not by addition of other glycosaminoglycans. PMID:18061161 When the amino acid sequence of the putative heparin-binding site was modified by in vitro mutagenesis, the resulting protein exhibited decreased affinity for heparin and reduced activity in the cell-binding assay.
GO:0044291 cell-cell contact zone	IDA PMID:18061161 The cell surface receptor FGFRL1 forms constitutive dimers t...	ACCEPT	Summary: FGFRL1 is enriched at cell-cell contact sites when overexpressed in cultured cells [PMID:18061161], consistent with its role as a cell adhesion molecule similar to nectins. Reason: This cellular component annotation is supported by direct experimental observation of FGFRL1 enrichment at cell-cell contact sites. Supporting Evidence: PMID:18061161 If overexpressed in cultivated cells, FGFRL1 was found to be enriched at cell-cell contact sites.
GO:0098742 obsolete cell-cell adhesion via plasma-membrane adhesion molecules	IMP PMID:18061161 The cell surface receptor FGFRL1 forms constitutive dimers t...	MODIFY	Summary: FGFRL1 promotes cell adhesion through its extracellular Ig-like domains. The adhesion is mediated by heparan sulfate and resembles nectin-like cell adhesion [PMID:18061161]. The GO term GO:0098742 is now obsolete and should be replaced with GO:0098609 (cell-cell adhesion). Reason: The underlying biology is correct and well-supported -- FGFRL1 is a cell adhesion molecule. However, GO:0098742 has been obsoleted because it "represents a method of annotation rather than a distinct biological process." The replacement term GO:0098609 (cell-cell adhesion) should be used. Proposed replacements: cell-cell adhesion Supporting Evidence: PMID:18061161 The extracellular domain of recombinant FGFRL1 promoted cell adhesion, but not cell spreading, when coated on plastic surfaces... With its dimeric structure and its adhesion promoting properties, FGFRL1 resembles the nectins, a family of cell adhesion molecules found at cell-cell junctions.
GO:0005794 Golgi apparatus	IDA PMID:18061161 The cell surface receptor FGFRL1 forms constitutive dimers t...	ACCEPT	Summary: FGFRL1 can be found in the Golgi apparatus as part of its trafficking through the secretory pathway. UniProt notes it is "Predominantly localized in the plasma membrane but also detected in the Golgi and in secretory vesicles." The reference PMID:18061161 addresses FGFRL1 cell surface biology but the Golgi localization is more directly attributed to PMID:12813049 and the deep research which describes FGFRL1 in Golgi/ER contexts. Reason: Golgi localization is consistent with FGFRL1 being a transmembrane protein that traffics through the secretory pathway. UniProt records this localization with experimental evidence (ECO:0000269\|PubMed:12813049). Supporting Evidence: PMID:12813049 When expressed in cultured cells as a fusion protein with green fluorescent protein, FGFRL1 was specifically localized to the plasma membrane where it might interact with FGF ligands.
GO:0030133 transport vesicle	IDA PMID:18061161 The cell surface receptor FGFRL1 forms constitutive dimers t...	ACCEPT	Summary: FGFRL1 is found in transport vesicles during its trafficking between cellular compartments. FGFRL1 contains a C-terminal tyrosine-based motif (PKLYPKLYTDI) that mediates rapid trafficking from the plasma membrane into endosomes and lysosomes. UniProt notes detection "in secretory vesicles." Reason: Transport vesicle localization is consistent with FGFRL1's known dynamic trafficking behavior. The cytoplasmic tail contains sorting motifs that mediate rapid endocytosis, and UniProt records detection in secretory vesicles. Supporting Evidence: file:human/FGFRL1/FGFRL1-deep-research.md In normal FGFRL1, these signals mediate rapid trafficking of the receptor from the plasma membrane into endosomes and lysosomes.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-5654510	ACCEPT	Summary: Plasma membrane localization annotation from Reactome pathway "FGFRL1 binds SPRED1/2." FGFRL1 interacts with SPRED proteins at the plasma membrane [Reactome:R-HSA-5654510]. Reason: Accurate cellular component annotation based on curated Reactome pathway information.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-5654511	ACCEPT	Summary: Plasma membrane localization annotation from Reactome pathway "FGFRL1 dimer binds FGFs." FGFRL1 dimers bind FGF ligands at the plasma membrane [Reactome:R-HSA-5654511]. Reason: Accurate cellular component annotation based on curated Reactome pathway information.
GO:0005007 fibroblast growth factor receptor activity	IDA PMID:12813049 Characterization of FGFRL1, a novel fibroblast growth factor...	MODIFY	Summary: This IDA annotation of FGF receptor activity was made based on PMID:12813049 which showed FGFRL1 binds FGF2 and heparin. However, the same paper explicitly concludes FGFRL1 lacks the kinase domain and acts as a decoy receptor, not a signaling receptor. Reason: The paper [PMID:12813049] that supports this annotation actually concludes that FGFRL1 "lacked the intracellular protein tyrosine kinase domain required for signal transduction" and "acts as a decoy receptor for FGF ligands." The binding activity is real, but calling it "receptor activity" (which implies signal transduction) is inappropriate. Should be annotated as FGF binding. Proposed replacements: fibroblast growth factor binding Supporting Evidence: PMID:12813049 Similar to FGF receptors, the expressed protein interacted specifically with heparin and with FGF2. PMID:12813049 However, it lacked the intracellular protein tyrosine kinase domain required for signal transduction by transphosphorylation.
GO:0005886 plasma membrane	IDA PMID:12813049 Characterization of FGFRL1, a novel fibroblast growth factor...	ACCEPT	Summary: FGFRL1 plasma membrane localization demonstrated by GFP fusion protein expression in cultured cells [PMID:12813049]. Reason: Accurate cellular component annotation with direct experimental support from GFP fusion localization studies. Supporting Evidence: PMID:12813049 When expressed in cultured cells as a fusion protein with green fluorescent protein, FGFRL1 was specifically localized to the plasma membrane where it might interact with FGF ligands.
GO:0008201 heparin binding	IDA PMID:12813049 Characterization of FGFRL1, a novel fibroblast growth factor...	ACCEPT	Summary: FGFRL1 specifically binds heparin, as demonstrated by recombinant protein produced in a baculovirus system [PMID:12813049]. This heparin binding activity is shared with canonical FGFRs and is functionally important for both FGF binding and cell adhesion. Reason: Accurate molecular function annotation with direct experimental support. Heparin binding is a well-established core function of FGFRL1. Supporting Evidence: PMID:12813049 Similar to FGF receptors, the expressed protein interacted specifically with heparin and with FGF2.
GO:0001822 kidney development	IEA	NEW	Summary: FGFRL1 is essential for metanephric kidney development. Fgfrl1 knockout mice show nearly complete absence of metanephric kidneys, with dramatic reduction of ureteric branching and lack of mesenchymal-to-epithelial transition [PMID:22432025]. FGFRL1 is expressed throughout kidney development in mesenchyme, ureteric bud, and nascent nephrons [PMID:22432025, PMID:21616146]. Reason: Kidney development is one of the most striking phenotypes of FGFRL1 loss of function. This annotation is not present in the existing GOA data despite strong evidence from multiple publications. While this is a developmental process rather than a core molecular function, it is a key biological process for FGFRL1. Supporting Evidence: PMID:22432025 However, the most striking phenotype of the Fgfrl1 deficient mice is the nearly complete absence of the metanephric kidneys. PMID:22432025 Fgfrl1 deficiency leads to a dramatic reduction of ureteric branching and to a lack of mesenchymal-to-epithelial transition in the nephrogenic mesenchyme PMID:21616146 FGFRL1 is a member of the fibroblast growth factor receptor family. It plays an essential role during branching morphogenesis of the metanephric kidneys, as mice with a targeted deletion of the Fgfrl1 gene show severe kidney dysplasia.
GO:0040037 negative regulation of fibroblast growth factor receptor signaling pathway	IEA	NEW	Summary: FGFRL1 acts as a decoy receptor that negatively regulates FGF signaling by sequestering FGF ligands away from canonical FGFRs. Knockdown of FGFRL1 increases FGFR signaling, while overexpression attenuates it [PMID:35053442]. This function is further supported by the Reactome pathway annotation [Reactome:R-HSA-5654511]. Reason: This is a core biological process for FGFRL1 that captures its primary regulatory role as a decoy receptor. The existing GO:0008543 annotation incorrectly implies direct participation in FGF signaling, when FGFRL1 actually negatively regulates the pathway. Supporting Evidence: PMID:35053442 Functional studies indicated that FGFRL1-KD in PC3M cells increases FGFR signaling, whereas FGFRL1 overexpression attenuates it, supporting decoy receptor actions of membrane-localized FGFRL1 PMID:12813049 Taken together our data are consistent with the view that FGFRL1 acts as a decoy receptor for FGF ligands. Reactome:R-HSA-5654511 FGFRL1 has been postulated to act as a decoy receptor that sequesters ligand away from canonical FGF receptors

Gene Description

Existing Annotations Review

Core Functions

FGF ligand binding and sequestration (decoy receptor function). FGFRL1 binds multiple FGF ligands through its extracellular Ig-like domains, sequestering them from canonical FGFRs and thereby negatively modulating FGF signaling.

Cell-cell adhesion through constitutive homodimerization and heparan sulfate-mediated interactions. FGFRL1 forms constitutive homodimers at the cell surface and promotes cell adhesion via heparan sulfate proteoglycans, resembling nectin-family adhesion molecules.

Heparin/heparan sulfate binding. FGFRL1 binds heparin and heparan sulfate through a basic region in its extracellular domain, which is required for both FGF co-receptor function and cell adhesion activity.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

FGFRL1: Structure, Primary Function, and Evolutionary Perspective

FGFRL1: A Kinase-Dead FGF Receptor-like Protein — Mechanism of Signaling, Adhesion, and Fusion

OpenScientist prompt: FGFRL1 kinase-dead signaling mechanism

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