FGFR signaling pathway module

Secreted FGF ligands, presented by heparan sulfate (paracrine FGFs) or by alpha/beta-Klotho co-receptors (endocrine FGFs), activate one or more FGFR receptor tyrosine kinase paralogs. The activated receptor phosphorylates the FRS2-family docking protein, which recruits GRB2-SOS to drive Ras-MAPK signalling and GRB2-GAB1-p85 to engage PI3K, while PLC-gamma binds the receptor directly and hydrolyses PIP2. The kinase-less paralog-like FGFRL1 attenuates signalling by sequestering ligand.

MODULE:fgfr_signalingDRAFTSignaling Pathwaymodules/fgfr_signaling.yaml

fibroblast growth factor receptor signaling pathwayGO:0008543

file:modules/fgfr_signaling-deep-research-falcon.md

FGFR signaling pathway Falcon module review

Falcon/Edison module review generated 2026-06-28 is linked as supporting evidence for module boundaries, core mechanism, variation, constraints, and failure modes; open questions in that report require manual review before promotion to curated knowledge gaps.

GO:0008543

fibroblast growth factor receptor signaling pathway

The module is grounded in the GO biological process term for fibroblast growth factor receptor signaling pathway.

PANTHER:PTN004704281

PAINT node PTN004704281 for the eumetazoan FGFR clade

Local PAINT IBD node in PTHR24416 (taxon Eumetazoa) with propagated terms P:GO:0008284, P:GO:0008543, P:GO:0043410; the GO:0008543 row is seeded by human FGFR1-4, their rodent and zebrafish orthologs, Drosophila breathless (FBgn0285896) and heartless (FBgn0010389), and C. elegans egl-15 (WBGene00001184). PAINT date 20250904.

PANTHER:PTN000699279

PAINT node PTN000699279 for the deuterostome FGFR clade

Local PAINT IBD node in PTHR24416 (taxon Deuterostomia) with propagated terms F:GO:0005007 and F:GO:0017134, seeded by FGFR1, FGFR2, FGFR3 and FGFR4. PAINT date 20250904.

PANTHER:PTN001230349

PAINT node PTN001230349 for receptor tyrosine kinases

Local PAINT IBD node in PTHR24416 with propagated terms C:GO:0005886, C:GO:0043235, F:GO:0004714, P:GO:0007169; PAINT date 20260529.

PANTHER:PTN000160075

PAINT node PTN000160075 for the FGF ligand family

Local PAINT IBD node in PTHR11486 with propagated terms including F:GO:0005104, F:GO:0008083, P:GO:0008543 and C:GO:0005576.

PANTHER:PTN005273574

PAINT node PTN005273574 for GRB2

Local PAINT IBD node in PTHR46037 with propagated terms C:GO:0005737, C:GO:0005886, C:GO:0008180, F:GO:0001784, F:GO:0005154, P:GO:0007165; PAINT date 20260530.

PANTHER:PTN008302071

PAINT node PTN008302071 for PIK3R1

Local PAINT IBD node in PTHR10155 with propagated terms C:GO:0005943; PAINT date 20240516.

PMID:16597617

Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family.

Establishes the ligand-by-receptor-paralog (and splice-isoform) specificity matrix for the whole mammalian FGF family, the basis for modelling receptor paralogs as a union of overlapping alternatives rather than as interchangeable copies.

Paralog union modelling (2026-09-30). The vertebrate FGF system is a whole-genome-duplication expansion: four receptor kinases (FGFR1-4), about eighteen secreted FGF ligands, two FRS docking proteins (FRS2, FRS3) and two SOS Ras GEFs (SOS1, SOS2), whereas protostomes carry one or two receptors (Drosophila breathless and heartless, C. elegans egl-15). Each step that is carried by a paralog group is therefore modelled as a variant set with axis "paralog" and selection ONE_OR_MORE: a concrete realization (a cell type, tissue, or species) uses any non-empty subset of the paralogs, and the module step as a whole is the union of what the paralogs do. Shared ancestral function is recorded once per paralog through the common PAINT nodes (PTN004704281, PTN000699279, PTN001230349), while lineage-specific nodes (PTN002814653 for FGFR1, PTN004704289 for FGFR4) and paralog-specific features (IIIb/IIIc splicing in FGFR1-3 only, FGFR4 recycling and FGF19/beta-Klotho bile-acid signalling, FGFR1c/Klotho FGF23 signalling) are recorded on the individual variant. Paralogs are not assumed to be interchangeable: the union says that each one can realize the step, not that each can substitute for every other in every context. FGFRL1 (sometimes called FGFR5) shares the FGFR ectodomain architecture but sits in a different PANTHER family (PTHR19890) and lacks a kinase domain, so it cannot satisfy the receptor kinase step and is modelled as a separate optional negative-regulatory part rather than as a fifth receptor variant. Heparan sulfate is a glycan cofactor, not a gene product, and is recorded in step descriptions rather than as an annoton. Negative feedback is split by scope: the FGFR-proximal attenuators IL17RD/SEF and CBL (recruited through FRS2-GRB2) are modelled here as an optional attenuation part, while Sprouty/SPRED and DUSP6, which act on Ras-RAF and ERK downstream of many receptors, are modelled in MODULE:erk_cascade. The context-dependent JAK-STAT output is outside the current boundary. The PI3K output part names GAB1 as the GRB2-recruited scaffold, but GAB1 is not yet an annoton there: it has no gene review here, so only the p85 regulatory subunit (PIK3R1) is grounded for now. Falcon integration (2026-06-28): Falcon findings are linked as evidence and family-level support; machine-generated Falcon citations remain curation support and are not manually adjudicated here.

20Nodes

8Parts

4Variant Sets

11Variants

18Annotons

8Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✓ present

fgfr_signaling-deep-research-falcon.md (falcon)

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Function consistency and core coverage

25 gene-function check(s) reflected in core functions · 0 conflict(s) · 19 evidence or coverage gap(s) (45 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

Annoton	Participant	Function	Assessment
paracrine_fgf_ligand	FGF1 UniProtKB:P05230 Family Representative	fibroblast growth factor receptor binding GO:0005104	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
paracrine_fgf_ligand	FGF2 UniProtKB:P09038 Family Representative	fibroblast growth factor receptor binding GO:0005104	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
paracrine_fgf_ligand	FGF7 UniProtKB:P21781 Family Representative	fibroblast growth factor receptor binding GO:0005104	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
paracrine_fgf_ligand	FGF10 UniProtKB:O15520 Family Representative	fibroblast growth factor receptor binding GO:0005104	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
paracrine_fgf_ligand	FGF8 UniProtKB:P55075 Family Representative	fibroblast growth factor receptor binding GO:0005104	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
endocrine_fgf_ligand	FGF19 UniProtKB:O95750 Family Representative	fibroblast growth factor receptor binding GO:0005104	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
endocrine_fgf_ligand	FGF21 UniProtKB:Q9NSA1 Family Representative	fibroblast growth factor receptor binding GO:0005104	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
endocrine_fgf_ligand	FGF23 UniProtKB:Q9GZV9 Family Representative	fibroblast growth factor receptor binding GO:0005104	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
klotho_coreceptor	KL (alpha-Klotho) UniProtKB:Q9UEF7 Family Representative	coreceptor activity GO:0015026	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
klotho_coreceptor	KLB (beta-Klotho) UniProtKB:Q86Z14 Family Representative	coreceptor activity GO:0015026	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
fgfr1_receptor_kinase	FGFR1 UniProtKB:P11362 Family Representative	fibroblast growth factor receptor activity GO:0005007	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
fgfr2_receptor_kinase	FGFR2 UniProtKB:P21802 Family Representative	fibroblast growth factor receptor activity GO:0005007	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
fgfr3_receptor_kinase	FGFR3 UniProtKB:P22607 Family Representative	fibroblast growth factor receptor activity GO:0005007	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
fgfr4_receptor_kinase	FGFR4 UniProtKB:P22455 Family Representative	fibroblast growth factor receptor activity GO:0005007	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
protostome_fgfr_receptor_kinase	btl (Drosophila breathless) UniProtKB:Q09147 Family Representative	fibroblast growth factor receptor activity GO:0005007	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
protostome_fgfr_receptor_kinase	htl (Drosophila heartless) UniProtKB:Q07407 Family Representative	fibroblast growth factor receptor activity GO:0005007	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
protostome_fgfr_receptor_kinase	egl-15 (C. elegans) UniProtKB:Q10656 Family Representative	fibroblast growth factor receptor activity GO:0005007	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
grb2_adaptor	GRB2 UniProtKB:P62993 Family Representative	guanyl-nucleotide exchange factor adaptor activity GO:0005091	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
frs2_adaptor	FRS2 UniProtKB:Q8WU20 Family Representative	transmembrane receptor protein tyrosine kinase adaptor activity GO:0005068	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
frs3_adaptor	FRS3 UniProtKB:O43559 Family Representative	transmembrane receptor protein tyrosine kinase adaptor activity GO:0005068	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
sos1_ras_gef	SOS1 UniProtKB:Q07889 Family Representative	guanyl-nucleotide exchange factor activity GO:0005085	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
sos2_ras_gef	SOS2 UniProtKB:Q07890 Family Representative	guanyl-nucleotide exchange factor activity GO:0005085	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
pik3r1_p85_adaptor	PIK3R1 UniProtKB:P27986 Family Representative	1-phosphatidylinositol-3-kinase regulator activity GO:0046935	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
plcg1_phospholipase	PLCG1 UniProtKB:P19174 Family Representative	phosphatidylinositol-4,5-bisphosphate phospholipase C activity GO:0004435	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
fgfrl1_decoy	FGFRL1 UniProtKB:Q8N441 Family Representative	fibroblast growth factor binding GO:0017134	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
il17rd_receptor_inhibitor	IL17RD UniProtKB:Q8NFM7 Family Representative	signaling receptor inhibitor activity GO:0030547	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cbl_receptor_ubiquitination	CBL UniProtKB:P22681 Family Representative	ubiquitin protein ligase activity GO:0061630	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
paracrine_fgf_ligand	Paracrine FGF ligand paralogs PANTHER:PTHR11486 Family	fibroblast growth factor receptor binding GO:0005104	Family Review Missing No supported structured family review is available for PANTHER:PTHR11486.
endocrine_fgf_ligand	Endocrine FGF19-subfamily ligand paralogs PANTHER:PTHR11486 Family	fibroblast growth factor receptor binding GO:0005104	Family Review Missing No supported structured family review is available for PANTHER:PTHR11486.
klotho_coreceptor	Klotho and beta-Klotho co-receptor paralogs PANTHER:PTHR10353 Family	coreceptor activity GO:0015026	Family Review Missing No supported structured family review is available for PANTHER:PTHR10353.
fgfr1_receptor_kinase	FGFR1 orthologs PANTHER:PTHR24416:SF131 Family	fibroblast growth factor receptor activity GO:0005007	Family Scope Restricted GO:0004714 requires member-level assessment of residue site kinase_catalytic_triad; a family identifier does not establish that condition. Within the DDR clade the activity follows the kinase catalytic triad, which is kept everywhere except the dipteran Ddr node PTN002400510: Drosophila Ddr (Ala789, Ser897, Ser910) and Anopheles DDR fail the site and are predicted pseudokinases (not assayed). The PTN001230349 node assessment records the matching IKR recommendation. RESIDUE_DETERMINED means the term is true wherever the triad is intact; it is not the most specific term for vertebrate DDR1 and DDR2, whose reviews refine it to GO:0038062.
fgfr2_receptor_kinase	FGFR2 orthologs PANTHER:PTHR24416:SF130 Family	fibroblast growth factor receptor activity GO:0005007	Family Scope Restricted GO:0004714 requires member-level assessment of residue site kinase_catalytic_triad; a family identifier does not establish that condition. Within the DDR clade the activity follows the kinase catalytic triad, which is kept everywhere except the dipteran Ddr node PTN002400510: Drosophila Ddr (Ala789, Ser897, Ser910) and Anopheles DDR fail the site and are predicted pseudokinases (not assayed). The PTN001230349 node assessment records the matching IKR recommendation. RESIDUE_DETERMINED means the term is true wherever the triad is intact; it is not the most specific term for vertebrate DDR1 and DDR2, whose reviews refine it to GO:0038062.
fgfr3_receptor_kinase	FGFR3 orthologs PANTHER:PTHR24416:SF505 Family	fibroblast growth factor receptor activity GO:0005007	Family Scope Restricted GO:0004714 requires member-level assessment of residue site kinase_catalytic_triad; a family identifier does not establish that condition. Within the DDR clade the activity follows the kinase catalytic triad, which is kept everywhere except the dipteran Ddr node PTN002400510: Drosophila Ddr (Ala789, Ser897, Ser910) and Anopheles DDR fail the site and are predicted pseudokinases (not assayed). The PTN001230349 node assessment records the matching IKR recommendation. RESIDUE_DETERMINED means the term is true wherever the triad is intact; it is not the most specific term for vertebrate DDR1 and DDR2, whose reviews refine it to GO:0038062.
fgfr4_receptor_kinase	FGFR4 orthologs PANTHER:PTHR24416:SF343 Family	fibroblast growth factor receptor activity GO:0005007	Family Scope Restricted GO:0004714 requires member-level assessment of residue site kinase_catalytic_triad; a family identifier does not establish that condition. Within the DDR clade the activity follows the kinase catalytic triad, which is kept everywhere except the dipteran Ddr node PTN002400510: Drosophila Ddr (Ala789, Ser897, Ser910) and Anopheles DDR fail the site and are predicted pseudokinases (not assayed). The PTN001230349 node assessment records the matching IKR recommendation. RESIDUE_DETERMINED means the term is true wherever the triad is intact; it is not the most specific term for vertebrate DDR1 and DDR2, whose reviews refine it to GO:0038062.
protostome_fgfr_receptor_kinase	Protostome FGFR homologs PANTHER:PTHR24416:SF550 Family	fibroblast growth factor receptor activity GO:0005007	Family Scope Restricted GO:0004714 requires member-level assessment of residue site kinase_catalytic_triad; a family identifier does not establish that condition. Within the DDR clade the activity follows the kinase catalytic triad, which is kept everywhere except the dipteran Ddr node PTN002400510: Drosophila Ddr (Ala789, Ser897, Ser910) and Anopheles DDR fail the site and are predicted pseudokinases (not assayed). The PTN001230349 node assessment records the matching IKR recommendation. RESIDUE_DETERMINED means the term is true wherever the triad is intact; it is not the most specific term for vertebrate DDR1 and DDR2, whose reviews refine it to GO:0038062.
grb2_adaptor	GRB2 adaptor family/ortholog group PANTHER:PTHR46037 Family	guanyl-nucleotide exchange factor adaptor activity GO:0005091	Family Review Missing No supported structured family review is available for PANTHER:PTHR46037.
frs2_adaptor	FRS2 orthologs PANTHER:PTHR21258:SF40 Family	transmembrane receptor protein tyrosine kinase adaptor activity GO:0005068	Family Review Missing No supported structured family review is available for PANTHER:PTHR21258:SF40.
frs3_adaptor	FRS3 orthologs PANTHER:PTHR21258:SF39 Family	transmembrane receptor protein tyrosine kinase adaptor activity GO:0005068	Family Review Missing No supported structured family review is available for PANTHER:PTHR21258:SF39.
sos1_ras_gef	SOS1 orthologs PANTHER:PTHR23113:SF168 Family	guanyl-nucleotide exchange factor activity GO:0005085	Family Review Missing No supported structured family review is available for PANTHER:PTHR23113:SF168.
sos2_ras_gef	SOS2 orthologs PANTHER:PTHR23113:SF150 Family	guanyl-nucleotide exchange factor activity GO:0005085	Family Review Missing No supported structured family review is available for PANTHER:PTHR23113:SF150.
pik3r1_p85_adaptor	PIK3R1 orthologs PANTHER:PTHR10155:SF3 Family	1-phosphatidylinositol-3-kinase regulator activity GO:0046935	Family Review Missing No supported structured family review is available for PANTHER:PTHR10155:SF3.
plcg1_phospholipase	PLCG1 orthologs PANTHER:PTHR10336:SF173 Family	phosphatidylinositol-4,5-bisphosphate phospholipase C activity GO:0004435	Family Supported Family review supports GO:0004435 FAMILY_WIDE. Every reviewed member (fungal PLC1/plc1, PLCG1, PLCG2) accepts it. fgfr_signaling selects SF173 (PLCG1) and myo_inositol_and_inositol_phosphate_biosynthesis selects SF36 (fungal PLC).
fgfrl1_decoy	FGFRL1 orthologs PANTHER:PTHR19890:SF10 Family	fibroblast growth factor binding GO:0017134	Family Review Missing No supported structured family review is available for PANTHER:PTHR19890:SF10.
il17rd_receptor_inhibitor	IL17RD orthologs PANTHER:PTHR15583:SF14 Family	signaling receptor inhibitor activity GO:0030547	Family Review Missing No supported structured family review is available for PANTHER:PTHR15583:SF14.
cbl_receptor_ubiquitination	CBL orthologs PANTHER:PTHR23007:SF5 Family	ubiquitin protein ligase activity GO:0061630	Family Review Missing No supported structured family review is available for PANTHER:PTHR23007:SF5.

Feedback loops (advisory, prose-driven: a regulator counts as "feedback" when its own description says so)

✓ every negative regulator described as feedback has an upstream edge closing the loop.

fgfrl1_decoy_attenuation ⊣ fgf_fgfr_binding [input]
fgfrl1_decoy_attenuation is a negative regulator with no upstream edge (not described as feedback)
fgfr_receptor_attenuation ⊣ fgfr_receptor_activation [closed]
fgfr_receptor_attenuation is regulated by frs2_grb2_scaffold: feedback loop closed

Gene-review completeness (25/27 grounded genes reviewed)

13 complete review(s) · 24 with deep research · 2 missing review · 1 reviewed but lacking deep research

Gene	Review	Complete	Deep research
btl Q09147	✓	90/91	✓
CBL P22681	✓	290/306	✓
FGF1 P05230	✓	✓	✓
FGF10 O15520	✓	155/156	✓
FGF19 O95750	✓	✓	✓
FGF2 P09038	✓	307/310	✓
FGF21 Q9NSA1	✓	✓	✓
FGF23 Q9GZV9	✓	✓	✓
FGF7 P21781	✓	✓	✓
FGF8 P55075	✓	193/195	✗
FGFR1 P11362	✓	✓	✓
FGFR2 P21802	✓	222/229	✓
FGFR3 P22607	✓	439/440	✓
FGFR4 P22455	✓	127/128	✓
FGFRL1 Q8N441	✓	25/27	✓
FRS2 Q8WU20	✓	✓	✓
FRS3 O43559	✓	✓	✓
GRB2 P62993	✓	✓	✓
IL17RD Q8NFM7	✓	18/20	✓
KL Q9UEF7	✓	✓	✓
KLB Q86Z14	✓	✓	✓
PIK3R1 P27986	✓	413/415	✓
PLCG1 P19174	✓	232/233	✓
htl (Drosophila heartless) Q07407	✗	—	—
egl-15 (C. elegans) Q10656	✗	—	—
SOS1 Q07889	✓	✓	✓
SOS2 Q07890	✓	✓	✓

Tree

FGFR signaling pathwaySignaling Pathwayfgfr_signaling

Parts
1. 1. ligand and co-receptor engagement
2. FGF ligand and co-receptor engage FGFRRegulatory Stepfgf_fgfr_binding
  
  Variants
  1. FGF ligand paralog classes and their co-receptors by paralog (One Or More)
    
    Paracrine FGF with heparan sulfateRegulatory Stepparacrine_fgf_variant
    
    Annotons
    
    Paracrine FGF ligand Family: Paracrine FGF ligand paralogs
    
    Endocrine FGF with Klotho co-receptorRegulatory Stependocrine_fgf_variant
    
    Annotons
    
    Endocrine FGF ligand Family: Endocrine FGF19-subfamily ligand paralogs
    
    Klotho-family co-receptor Family: Klotho and beta-Klotho co-receptor paralogs
3. 2. receptor tyrosine kinase activation
4. FGFR paralog activation and autophosphorylationRegulatory Stepfgfr_receptor_activation
  
  Variants
  1. FGFR receptor tyrosine kinase paralogs by paralog (One Or More)
    
    FGFR1Regulatory Stepfgfr1_variant
    
    Annotons
    
    FGFR1 receptor tyrosine kinase Family: FGFR1 orthologs
    
    FGFR2Regulatory Stepfgfr2_variant
    
    Annotons
    
    FGFR2 receptor tyrosine kinase Family: FGFR2 orthologs
    
    FGFR3Regulatory Stepfgfr3_variant
    
    Annotons
    
    FGFR3 receptor tyrosine kinase Family: FGFR3 orthologs
    
    FGFR4Regulatory Stepfgfr4_variant
    
    Annotons
    
    FGFR4 receptor tyrosine kinase Family: FGFR4 orthologs
    
    Protostome FGFR (breathless, heartless, egl-15)Regulatory Stepprotostome_fgfr_variant
    
    Annotons
    
    Protostome FGFR receptor tyrosine kinase Family: Protostome FGFR homologs
5. 3. FRS docking protein and GRB2 scaffold assembly
6. FRS/GRB2 scaffold assemblyRegulatory Stepfrs2_grb2_scaffold
  
  Annotons
  - GRB2 adaptor Family: GRB2 adaptor family/ortholog group
  Variants
  1. FRS docking protein paralogs by paralog (One Or More)
    
    FRS2Regulatory Stepfrs2_variant
    
    Annotons
    
    FRS2 docking protein Family: FRS2 orthologs
    
    FRS3Regulatory Stepfrs3_variant
    
    Annotons
    
    FRS3 docking protein Family: FRS3 orthologs
7. 4. Ras-MAPK output
8. SOS-driven Ras-MAPK outputRegulatory Stepfgfr_ras_mapk_output
  
  Variants
  1. SOS Ras GEF paralogs by paralog (One Or More)
    
    SOS1Regulatory Stepsos1_variant
    
    Annotons
    
    SOS1 Ras GEF Family: SOS1 orthologs
    
    SOS2Regulatory Stepsos2_variant
    
    Annotons
    
    SOS2 Ras GEF Family: SOS2 orthologs
9. 5. PI3K output
10. GAB1-p85 PI3K outputRegulatory Stepfgfr_pi3k_output
  
  Annotons
  - PIK3R1 p85 regulatory subunit Family: PIK3R1 orthologs
11. 6. PLC-gamma output optional
12. PLC-gamma outputRegulatory Stepfgfr_plcg_output
  
  Annotons
  - PLCG1 phospholipase C-gamma Family: PLCG1 orthologs
13. 7. decoy-receptor attenuation optional
14. FGFRL1 decoy-receptor attenuationRegulatory Stepfgfrl1_decoy_attenuation
  
  Annotons
  - FGFRL1 decoy receptor Family: FGFRL1 orthologs
15. 8. receptor-level attenuation optional
16. Receptor-level attenuation by SEF and CBLRegulatory Stepfgfr_receptor_attenuation
  
  Annotons
  - IL17RD/SEF receptor-level inhibitor Family: IL17RD orthologs
  - CBL ubiquitination of FGFR and FRS2 Family: CBL orthologs

Details

Context

metazoaNCBITaxon:33208

plasma membraneGO:0005886 cytosolGO:0005829

FGFR signaling pathwaySignaling Pathwayfgfr_signaling

fibroblast growth factor receptor signaling pathwayGO:0008543

Context

metazoaNCBITaxon:33208

plasma membraneGO:0005886 cytosolGO:0005829

Connections

fgf_fgfr_binding -> fgfr_receptor_activation Causes

Ligand-co-receptor engagement dimerizes and activates the receptor kinase.

fgfr_receptor_activation -> frs2_grb2_scaffold Causes

The activated receptor phosphorylates the FRS docking protein, recruiting GRB2.

frs2_grb2_scaffold -> fgfr_ras_mapk_output Causes

GRB2 brings SOS to the membrane to activate Ras.

frs2_grb2_scaffold -> fgfr_pi3k_output Causes

GRB2 recruits GAB1, which engages p85-PI3K.

fgfr_receptor_activation -> fgfr_plcg_output Causes

PLC-gamma binds the receptor directly, independently of FRS2.

fgfrl1_decoy_attenuation -> fgf_fgfr_binding Negatively Regulates

FGFRL1 sequesters FGF ligands away from signalling-competent FGFRs.

frs2_grb2_scaffold -> fgfr_receptor_attenuation Provides Input For

Phospho-FRS2-bound GRB2 recruits CBL to the activated receptor complex.

fgfr_receptor_attenuation -> fgfr_receptor_activation Negatively Regulates

SEF lowers FGFR1 phosphorylation and CBL ubiquitinates FGFR and FRS2 for degradation.

Part 1: ligand and co-receptor engagement

FGF ligand and co-receptor engage FGFRRegulatory Stepfgf_fgfr_binding

A secreted FGF binds the FGFR ectodomain together with a co-receptor. Paracrine FGFs bind heparan sulfate with high affinity, and heparan sulfate is required for the active asymmetric receptor dimer. Endocrine FGFs (FGF19, FGF21, FGF23) have low heparan sulfate affinity, circulate systemically, and need an alpha- or beta-Klotho co-receptor to form a high-affinity complex.

Variant set: FGF ligand paralog classes and their co-receptors by paralog (One Or More)

PMID:17623664

The fibroblast growth factor (FGF) 19 subfamily of ligands, FGF19, FGF21, and FGF23, function as hormones that regulate bile acid, fatty acid, glucose, and phosphate metabolism in target organs through activating FGF receptors (FGFR1-4).

The FGF ligand paralogs split into heparan-sulfate-dependent paracrine FGFs and Klotho-dependent endocrine FGFs. A given tissue can respond to either or both classes, so the step is the union of the two. Intracellular FGFs (FGF11-14, also in PTHR11486) do not signal through FGFRs and are excluded.

Paracrine FGF with heparan sulfateRegulatory Stepparacrine_fgf_variant

Canonical paracrine FGFs (FGF1, FGF2, FGF7, FGF8, FGF10 and others) bind the receptor with heparan sulfate proteoglycan as cofactor. Ligand choice is constrained by receptor paralog and IIIb/IIIc isoform; FGF1 is the only ligand that activates every receptor isoform, while FGF7 and FGF10 are selective for the epithelial FGFR2 IIIb isoform. Paracrine FGFs bind heparin/heparan sulfate directly (heparin binding, GO:0008201).

Annotons

Paracrine FGF ligand

paracrine_fgf_ligand

Participant: Family: Paracrine FGF ligand paralogs

Family:

Paracrine FGF ligand paralogsPANTHER:PTHR11486

Representative Members: FGF1UniProtKB:P05230 FGF2UniProtKB:P09038 FGF7UniProtKB:P21781 FGF10UniProtKB:O15520 FGF8UniProtKB:P55075

Function

fibroblast growth factor receptor bindingGO:0005104

Secreted paracrine ligand that binds FGFR together with heparan sulfate and triggers receptor dimerization.

PMID:8663044

These studies demonstrate that FGF 1 is the only FGF that can activate all FGF receptor splice variants.

PMID:16597617

Completes the mitogenesis-based receptor-specificity matrix for FGFs 10-23 against the seven principal FGFR isoforms.

file:genes/human/FGF1/FGF1-ai-review.yaml

FGF1 review: core functions FGFR binding (GO:0005104), heparin binding (GO:0008201) and growth factor activity in the extracellular region.

file:genes/human/FGF2/FGF2-ai-review.yaml

FGF2 review: core functions FGFR binding (GO:0005104) and heparin binding (GO:0008201, NEW IDA from the FGF2-FGFR1-heparin ternary structure).

file:genes/human/FGF7/FGF7-ai-review.yaml

FGF7 review: core function type 2 FGF receptor binding (GO:0005111), i.e. selective for the FGFR2 IIIb isoform.

file:genes/human/FGF10/FGF10-ai-review.yaml

FGF10 review: core function type 2 FGF receptor binding (GO:0005111, FGFR2 IIIb, supported by the FGF10-FGFR2b crystal structure); FGF10 also activates FGFR1b.

Endocrine FGF with Klotho co-receptorRegulatory Stependocrine_fgf_variant

Endocrine FGF19, FGF21 and FGF23 require a Klotho-family co-receptor bound to the FGFR. Which receptor paralog and which Klotho is expressed decides the target tissue: FGF23 acts mainly through Klotho-FGFR1c in kidney and parathyroid, FGF21 mainly through beta-Klotho-FGFR1c in adipose tissue (it can also signal through beta-Klotho bound to FGFR2c or FGFR3c, but not efficiently through FGFR4), and FGF19 through beta-Klotho-FGFR4 in hepatocytes. These ligands act as circulating hormones (hormone activity, GO:0005179) and, unlike paracrine FGFs, are largely non-mitogenic.

Annotons

Endocrine FGF ligand

endocrine_fgf_ligand

Participant: Family: Endocrine FGF19-subfamily ligand paralogs

Family:

Endocrine FGF19-subfamily ligand paralogsPANTHER:PTHR11486

Representative Members: FGF19UniProtKB:O95750 FGF21UniProtKB:Q9NSA1 FGF23UniProtKB:Q9GZV9

Function

fibroblast growth factor receptor bindingGO:0005104

Circulating hormone-like FGF that binds a Klotho-FGFR complex.

PMID:17623664

Both FGF19 and FGF21 can signal through FGFR1-3 bound by betaKlotho and increase glucose uptake in adipocytes expressing FGFR1.

file:genes/human/FGF19/FGF19-ai-review.yaml

FGF19 review: core function FGFR binding (GO:0005104) via the beta-Klotho-FGFR4 complex.

file:genes/human/FGF21/FGF21-ai-review.yaml

FGF21 review: core functions FGFR binding (GO:0005104) and hormone activity (GO:0005179); signals through beta-Klotho-FGFR1c but not efficiently through FGFR4.

file:genes/human/FGF23/FGF23-ai-review.yaml

FGF23 review: core functions type 1 FGF receptor binding (GO:0005105, FGFR1c with alpha-Klotho) and hormone activity (GO:0005179).

Klotho-family co-receptor

klotho_coreceptor

Participant: Family: Klotho and beta-Klotho co-receptor paralogs

Family:

Klotho and beta-Klotho co-receptor paralogsPANTHER:PTHR10353

Representative Members: KL (alpha-Klotho)UniProtKB:Q9UEF7 KLB (beta-Klotho)UniProtKB:Q86Z14

Function

coreceptor activityGO:0015026

Locations

plasma membraneGO:0005886 extracellular regionGO:0005576

Single-pass transmembrane co-receptor that binds FGFR and confers high-affinity endocrine FGF binding.

PMID:16436388

Thus, Klotho functions as a cofactor essential for activation of FGF signaling by FGF23.

file:genes/human/KLB/KLB-ai-review.yaml

The KLB gene review assigns coreceptor activity (GO:0015026) as the core molecular function within FGF receptor signalling.

file:genes/human/KL/KL-ai-review.yaml

KL review: single core function coreceptor activity (GO:0015026) for FGF23; the shed ectodomain also acts as a co-receptor in trans; glycosidase activities judged over-annotated.

Part 2: receptor tyrosine kinase activation

FGFR paralog activation and autophosphorylationRegulatory Stepfgfr_receptor_activation

Ligand, co-receptor and heparan sulfate bring a primary and a secondary FGFR together; the kinase domains trans-autophosphorylate and create phosphotyrosine docking sites, including the C-terminal tyrosine (Y766 in FGFR1) that binds PLC-gamma. All four vertebrate paralogs and the protostome receptors have this core activity; the paralogs differ in ligand range, splice isoforms, co-receptor partners, tissue expression and trafficking.

Variant set: FGFR receptor tyrosine kinase paralogs by paralog (One Or More)

PMID:16597617

FGFs bind and activate alternatively spliced forms of four tyrosine kinase FGF receptors (FGFRs 1-4).

Union over the FGFR clade of PTHR24416. Every variant shares the ancestral FGF receptor activity recorded on PTN004704281 (Eumetazoa), PTN000699279 (Deuterostomia) and PTN001230349 (receptor tyrosine kinases). Many cells express more than one paralog, so a realization selects one or more variants.

FGFR1Regulatory Stepfgfr1_variant

Broadly expressed, mainly mesenchymal receptor. IIIb/IIIc splicing sets ligand preference. FGFR1c is the main receptor for the endocrine ligands FGF23 (with Klotho) and FGF21 (with beta-Klotho).

Annotons

FGFR1 receptor tyrosine kinase

fgfr1_receptor_kinase

Participant: Family: FGFR1 orthologs

Family:

FGFR1 orthologsPANTHER:PTHR24416:SF131

Representative Members: FGFR1UniProtKB:P11362

Function

fibroblast growth factor receptor activityGO:0005007

Locations

plasma membraneGO:0005886

FGF receptor tyrosine kinase that phosphorylates FRS2 and PLCG1; the paralog used by FGF21 and FGF23 endocrine signalling.

PMID:17623664

Both FGF19 and FGF21 can signal through FGFR1-3 bound by betaKlotho and increase glucose uptake in adipocytes expressing FGFR1.

file:genes/human/FGFR1/FGFR1-ai-review.yaml

FGFR1 review: core functions FGF receptor activity (GO:0005007), FGF binding and heparin binding; FGF23 activates FGFR1c in a Klotho-dependent fashion.

FGFR2Regulatory Stepfgfr2_variant

Main epithelial receptor. ESRP1/2-controlled IIIb splicing makes FGFR2b the receptor for mesenchyme-derived FGF7 and FGF10 in the reciprocal epithelial-mesenchymal loops of lung, limb and skin development.

Annotons

FGFR2 receptor tyrosine kinase

fgfr2_receptor_kinase

Participant: Family: FGFR2 orthologs

Family:

FGFR2 orthologsPANTHER:PTHR24416:SF130

Representative Members: FGFR2UniProtKB:P21802

Function

fibroblast growth factor receptor activityGO:0005007

Locations

plasma membraneGO:0005886

FGF receptor tyrosine kinase; the principal epithelial paralog.

file:genes/human/FGFR2/FGFR2-ai-review.yaml

The FGFR2 gene review assigns fibroblast growth factor receptor activity (GO:0005007) as the core molecular function, acting in FGF receptor signalling, lung development and bone development.

FGFR3Regulatory Stepfgfr3_variant

IIIb/IIIc-spliced receptor with prominent roles in growth-plate chondrocytes, where its signalling restrains proliferation, and in the inner ear.

Annotons

FGFR3 receptor tyrosine kinase

fgfr3_receptor_kinase

Participant: Family: FGFR3 orthologs

Family:

FGFR3 orthologsPANTHER:PTHR24416:SF505

Representative Members: FGFR3UniProtKB:P22607

Function

fibroblast growth factor receptor activityGO:0005007

Locations

plasma membraneGO:0005886

FGF receptor tyrosine kinase; the paralog that dominates in skeletal growth-plate signalling.

file:genes/human/FGFR3/FGFR3-ai-review.yaml

FGFR3 review: core function FGF receptor activity (GO:0005007), including the FGFR3-specific restraint of growth-plate chondrocyte proliferation and differentiation.

FGFR4Regulatory Stepfgfr4_variant

Has no IIIb/IIIc splice pair (IIIc-like only) and is reported to recycle to the cell surface more than FGFR1-3, although the common G388 form is still degraded after ligand binding. With beta-Klotho it is the hepatocyte receptor for FGF19, which represses CYP7A1 and bile acid synthesis; this role is recorded on an FGFR4-lineage PAINT node.

Annotons

FGFR4 receptor tyrosine kinase

fgfr4_receptor_kinase

Participant: Family: FGFR4 orthologs

Family:

FGFR4 orthologsPANTHER:PTHR24416:SF343

Representative Members: FGFR4UniProtKB:P22455

Function

fibroblast growth factor receptor activityGO:0005007

Processes

negative regulation of bile acid biosynthetic processGO:0070858

Locations

plasma membraneGO:0005886

FGF receptor tyrosine kinase; the paralog through which FGF19-beta-Klotho represses hepatic bile acid synthesis.

PMID:17623664

Additionally, both FGF19 and FGF21 bind to the betaKlotho-FGFR4 complex; however, only FGF19 signals efficiently through FGFR4.

PMID:12815072

a secreted growth factor that signals through the FGFR4 cell-surface receptor tyrosine kinase

file:genes/human/FGFR4/FGFR4-ai-review.yaml

FGFR4 review: core function FGF receptor activity (GO:0005007), including negative regulation of bile acid biosynthesis (GO:0070858) via FGF19 and beta-Klotho.

Protostome FGFR (breathless, heartless, egl-15)Regulatory Stepprotostome_fgfr_variant

Invertebrate FGF receptors that realize the same step without the vertebrate duplications: Drosophila breathless (tracheal branching) and heartless (mesoderm migration), and C. elegans egl-15 (sex myoblast migration, fluid homeostasis). They seed the eumetazoan FGFR node together with FGFR1-4.

Annotons

Protostome FGFR receptor tyrosine kinase

protostome_fgfr_receptor_kinase

Participant: Family: Protostome FGFR homologs

Family:

Protostome FGFR homologsPANTHER:PTHR24416:SF550

Representative Members: btl (Drosophila breathless)UniProtKB:Q09147 htl (Drosophila heartless)UniProtKB:Q07407 egl-15 (C. elegans)UniProtKB:Q10656

Function

fibroblast growth factor receptor activityGO:0005007

Locations

plasma membraneGO:0005886

Protostome FGF receptor tyrosine kinase that performs the same step outside vertebrates.

Part 3: FRS docking protein and GRB2 scaffold assembly

FRS/GRB2 scaffold assemblyRegulatory Stepfrs2_grb2_scaffold

The FRS docking protein is constitutively bound to the FGFR juxtamembrane region and is tyrosine-phosphorylated by the activated receptor. Its phosphotyrosines recruit GRB2, which brings SOS and GAB1 to the membrane. This constitutive FRS docking protein is what separates FGFR signalling from the SHC1-based adaptors used by most other RTKs.

Annotons

GRB2 adaptor

grb2_adaptor

Participant: Family: GRB2 adaptor family/ortholog group

Family:

GRB2 adaptor family/ortholog groupPANTHER:PTHR46037

Representative Members: GRB2UniProtKB:P62993

Function

guanyl-nucleotide exchange factor adaptor activityGO:0005091

SH2-SH3 adaptor that binds phospho-FRS through its SH2 domain and SOS or GAB1 through its SH3 domains.

file:genes/human/GRB2/GRB2-ai-review.yaml

The GRB2 gene review assigns guanyl-nucleotide exchange factor adaptor activity (GO:0005091) as a core function, bridging receptor phosphotyrosines to SOS.

Variant set: FRS docking protein paralogs by paralog (One Or More)

FRS2 is the main, broadly expressed docking protein; FRS3 is a paralog with the same PTB-domain docking architecture and FGFR binding. Both carry FGFR binding and RTK adaptor activity annotations in GOA, so either can realize the step.

FRS2Regulatory Stepfrs2_variant

Annotons

FRS2 docking protein

frs2_adaptor

Participant: Family: FRS2 orthologs

Family:

FRS2 orthologsPANTHER:PTHR21258:SF40

Representative Members: FRS2UniProtKB:Q8WU20

Function

transmembrane receptor protein tyrosine kinase adaptor activityGO:0005068

Membrane-anchored docking protein phosphorylated by FGFR that assembles the GRB2-SOS and GRB2-GAB1 complexes.

file:genes/human/FRS2/FRS2-ai-review.yaml

FRS2 review: core functions RTK adaptor activity (GO:0005068) and FGFR binding (GO:0005104); the PTB domain binds the FGFR juxtamembrane region without a phosphotyrosine.

FRS3Regulatory Stepfrs3_variant

Annotons

FRS3 docking protein

frs3_adaptor

Participant: Family: FRS3 orthologs

Family:

FRS3 orthologsPANTHER:PTHR21258:SF39

Representative Members: FRS3UniProtKB:O43559

Function

transmembrane receptor protein tyrosine kinase adaptor activityGO:0005068

FRS2 paralog able to dock on FGFR and recruit GRB2.

file:genes/human/FRS3/FRS3-ai-review.yaml

FRS3 review: core functions RTK adaptor activity (GO:0005068) and FGFR binding (GO:0005104); FRS3 binds FGFR1 directly through its PTB domain, recruits GRB2 and SHP2, and restores MAPK activation in Frs2-null cells.

Part 4: Ras-MAPK output

SOS-driven Ras-MAPK outputRegulatory Stepfgfr_ras_mapk_output

GRB2-bound SOS catalyses GDP/GTP exchange on Ras at the plasma membrane, starting the RAF-MEK-ERK cascade (modelled separately in erk_cascade).

Variant set: SOS Ras GEF paralogs by paralog (One Or More)

SOS1 and SOS2 are both GRB2-binding Ras GEFs. SOS1 carries the eukaryote-wide PAINT GEF node; SOS2 is included as the paralog that can realize the same step.

SOS1Regulatory Stepsos1_variant

Annotons

SOS1 Ras GEF

sos1_ras_gef

Participant: Family: SOS1 orthologs

Family:

SOS1 orthologsPANTHER:PTHR23113:SF168

Representative Members: SOS1UniProtKB:Q07889

Function

guanyl-nucleotide exchange factor activityGO:0005085

Processes

Ras protein signal transductionGO:0007265

Ras GEF recruited to the FRS2-GRB2 complex.

SOS2Regulatory Stepsos2_variant

Annotons

SOS2 Ras GEF

sos2_ras_gef

Participant: Family: SOS2 orthologs

Family:

SOS2 orthologsPANTHER:PTHR23113:SF150

Representative Members: SOS2UniProtKB:Q07890

Function

guanyl-nucleotide exchange factor activityGO:0005085

Processes

Ras protein signal transductionGO:0007265

SOS1 paralog that can provide the Ras GEF activity.

file:genes/human/SOS2/SOS2-ai-review.yaml

SOS2 review: core function guanyl-nucleotide exchange factor activity (GO:0005085) with its own experimental support; SOS2 is a less important, partly redundant paralog of SOS1.

Part 5: PI3K output

GAB1-p85 PI3K outputRegulatory Stepfgfr_pi3k_output

GRB2 bound to phospho-FRS2 recruits GAB1, whose phosphotyrosines bind the p85 regulatory subunit of class IA PI3K and activate AKT signalling.

Annotons

PIK3R1 p85 regulatory subunit

pik3r1_p85_adaptor

Participant: Family: PIK3R1 orthologs

Family:

PIK3R1 orthologsPANTHER:PTHR10155:SF3

Representative Members: PIK3R1UniProtKB:P27986

Function

1-phosphatidylinositol-3-kinase regulator activityGO:0046935

Regulatory subunit that couples the phospho-GAB1 scaffold to the class IA PI3K catalytic subunit.

Part 6: PLC-gamma output (optional)

PLC-gamma outputRegulatory Stepfgfr_plcg_output

PLC-gamma binds the phosphorylated C-terminal tyrosine of the receptor (Y766 in FGFR1) without FRS2, is phosphorylated, and hydrolyses PIP2 to DAG and IP3, giving PKC activation and Ca2+ release. The branch is optional because a receptor lacking the site still drives mitogenesis.

Annotons

PLCG1 phospholipase C-gamma

plcg1_phospholipase

Participant: Family: PLCG1 orthologs

Family:

PLCG1 orthologsPANTHER:PTHR10336:SF173

Representative Members: PLCG1UniProtKB:P19174

Function

phosphatidylinositol-4,5-bisphosphate phospholipase C activityGO:0004435

Phospholipase recruited directly to the activated receptor.

PMID:1379697

a fibroblast growth factor (FGF) receptor with a single point mutation at residue 766 replacing tyrosine with phenylalanine fails to associate with PLC gamma in response to FGF

file:genes/human/PLCG1/PLCG1-ai-review.yaml

PLCG1 review: core functions PIP2 phospholipase C activity (GO:0004435) and phosphotyrosine residue binding (GO:0001784); NEW IGI (with FGFR1) for FGF receptor signalling from the FGFR1 Y766F mutant.

Part 7: decoy-receptor attenuation (optional)

FGFRL1 decoy-receptor attenuationRegulatory Stepfgfrl1_decoy_attenuation

FGFRL1 has the three-Ig-domain FGFR ectodomain and binds FGF ligands and heparin, but has no kinase domain. It lowers signalling by sequestering ligand. It is kept separate from the receptor paralog union because it cannot perform the kinase step.

Annotons

FGFRL1 decoy receptor

fgfrl1_decoy

Participant: Family: FGFRL1 orthologs

Family:

FGFRL1 orthologsPANTHER:PTHR19890:SF10

Representative Members: FGFRL1UniProtKB:Q8N441

Function

fibroblast growth factor bindingGO:0017134

Processes

negative regulation of fibroblast growth factor receptor signaling pathwayGO:0040037

Locations

plasma membraneGO:0005886

Kinase-less FGFR relative that binds and sequesters FGF ligands.

file:genes/human/FGFRL1/FGFRL1-ai-review.yaml

The FGFRL1 gene review assigns fibroblast growth factor binding (GO:0017134) with negative regulation of FGF receptor signalling as the decoy-receptor core function.

Part 8: receptor-level attenuation (optional)

Receptor-level attenuation by SEF and CBLRegulatory Stepfgfr_receptor_attenuation

Two FGF-induced or signal-recruited proteins turn the activated receptor down. IL17RD/SEF, a transmembrane protein whose expression FGF signalling induces, associates with FGFR1 and FGFR2 (co-immunoprecipitation; direct binding is not established) and reduces FGFR1 and FRS2 tyrosine phosphorylation; a separate isoform-dependent activity retains activated MEK-ERK at the Golgi. CBL is recruited by GRB2 bound to phosphorylated FRS2 and ubiquitinates FGFR and FRS2, driving their internalisation and degradation.

Annotons

IL17RD/SEF receptor-level inhibitor

il17rd_receptor_inhibitor

Participant: Family: IL17RD orthologs

Family:

IL17RD orthologsPANTHER:PTHR15583:SF14

Representative Members: IL17RDUniProtKB:Q8NFM7

Function

signaling receptor inhibitor activityGO:0030547

Processes

negative regulation of fibroblast growth factor receptor signaling pathwayGO:0040037

Locations

plasma membraneGO:0005886

FGF-induced transmembrane feedback inhibitor acting at or above the receptor.

PMID:12958313

Co-immunoprecipitation and immunostaining experiments indicate that hSef interacts with FGFR1 and FGFR2 but not FGFR3.

PMID:12604616

Sef inhibits fibroblast growth factor signaling by inhibiting FGFR1 tyrosine phosphorylation and subsequent ERK activation.

file:genes/human/IL17RD/IL17RD-ai-review.yaml

IL17RD review core function signaling receptor inhibitor activity (GO:0030547) in negative regulation of FGFR signalling (GO:0040037); IL-17 receptor activity judged over-annotated because IL17RD remains an orphan receptor.

CBL ubiquitination of FGFR and FRS2

cbl_receptor_ubiquitination

Participant: Family: CBL orthologs

Family:

CBL orthologsPANTHER:PTHR23007:SF5

Representative Members: CBLUniProtKB:P22681

Function

ubiquitin protein ligase activityGO:0061630

Processes

negative regulation of fibroblast growth factor receptor signaling pathwayGO:0040037

Locations

plasma membraneGO:0005886

E3 ligase recruited through FRS2-GRB2 that ubiquitinates FGFR and FRS2 for down-regulation.

PMID:11997436

Grb2 bound to tyrosine-phosphorylated FRS2 alpha forms a ternary complex with Cbl by means of its Src homology 3 domains resulting in the ubiquitination of fibroblast growth factor (FGF) receptor and FRS2 alpha in response to FGF stimulation.

file:genes/human/CBL/CBL-ai-review.yaml

CBL review core function ubiquitin protein ligase activity (GO:0061630) in negative regulation of FGFR signalling (GO:0040037, NEW IDA from PMID:11997436).