FGF Family Signaling Pathways

Click on one of the FGF subfamilies below to see additional information about the FGF ligands belonging to each subfamily. Refer to the table below the pathway to see the reported receptor binding specificities for the different FGF ligands, their physiological functions, and the pathologies associated with mutations or amplification of different FGFs.

FGF Dimer
FGF Dimer
FGF R Dimer
FGF R Dimer
HSPG
HSPG
HSPG
HSPG
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FRS2
FRS2
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Cbl
Cbl
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GRB2
GRB2
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Src
Src
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Shb
Shb
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FRS2
FRS2
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SHP-2
SHP-2
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GRB2
GRB2
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SOS
SOS
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GRB2
GRB2
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Gab1
Gab1
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Shc
Shc
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GRB2
GRB2
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Crk
Crk
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SOS
SOS
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Ubiquitin-dependent
Degradation
Ubiquitin-dependent
Degradation
PLC-gamma
PLC-gamma
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PIP2
PIP2
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DAG
DAG
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IP3
IP3
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PKC
PKC
IP3 Receptor
IP3 Receptor
Ca2+
Ca2+
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Calmodulin
Calmodulin
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Calcineurin
Phosphatase
Calcineurin
Phosphatase
NFATC
NFATC
NFATC
NFATC
Cell Motility
Cell Motility
PI 3-K
PI 3-K
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PIP2
PIP2
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PIP3
PIP3
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PDK-1
PDK-1
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Akt/PKB
Akt/PKB
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GSK-3 beta
(Inactive)
GSK-3 beta
(Inactive)
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Bad
(Inactive)
Bad
(Inactive)
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Caspase-9
(Inactive)
Caspase-9
(Inactive)
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Anti-Apoptotic Signal
Anti-Apoptotic Signal
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FoxO
FoxO
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FoxO
FoxO
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Cell Survival
Cell Survival
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TSC1/2
(Inactive)
TSC1/2
(Inactive)
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Rheb
Rheb
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GTP
GTP
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mTORC1
mTORC1
p70 S6K
p70 S6K
RPS6
RPS6
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4EBP1
4EBP1
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eIF4E
eIF4E
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eIF4E
eIF4E
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4EBP1
4EBP1
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Protein Synthesis
Protein Synthesis
Jak
Jak
STAT
STAT
STAT Dimer
STAT Dimer
STAT Dimer
STAT Dimer
Cell Proliferation
Differentiation
Cell Proliferation
Differentiation
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Ras
Ras
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GDP
GDP
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Ras
Ras
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GTP
GTP
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Rac
Rac
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p38
p38
JNK
JNK
Transcription
Factor
Transcription
Factor
Stress Response
Stress Response
Raf
Raf
MEK1/2
MEK1/2
ERK1/2
ERK1/2
p90 RSK
p90 RSK
Transcription
Factor
Transcription
Factor
Cell Proliferation
Cell Proliferation
Transcription
Factor
Transcription
Factor
FGF
Inhibitors
FGF
Inhibitors
Negative Feedback
Negative Feedback
• FGF-1 subfamily members: FGF-1 and FGF-2.
• Both lack a classical secretory signal peptide and are secreted independently of the traditional ER-Golgi secretory pathway.
• Utilize heparin/HS as a co-factor to bind to FGF receptors.
• FGF-1 and FGF-2 are found in the nucleus of some cells.
• See the table below the pathway for additional information on the FGF-1 subfamily members including their suggested physiological functions and reported receptor binding specificities.
• FGF-4 subfamily members: FGF-4, FGF-5, and FGF-6.
• Have a cleavable N-terminal signal peptide.
• Utilize heparin/HS as a co-factor to bind to FGF receptors.
• See the table below the pathway for additional information on the FGF-4 subfamily members including their suggested physiological functions and reported receptor binding specificities.
• FGF-7 subfamily members: FGF-3, FGF-7, FGF-10, and FGF-22.
• Utilize heparin/HS as a co-factor to bind to FGF receptors.
• See the table below the pathway for additional information on the FGF-7 subfamily members including their suggested physiological functions and reported receptor binding specificities.
• FGF-8 subfamily members: FGF-8, FGF-17, and FGF-18.
• Have a cleavable N-terminal signal peptide.
• Utilize heparin/HS as a co-factor to bind to FGF receptors.
• Alternative splicing of FGF8 gives rise to four potential isoforms in human (FGF-8a, FGF-8b, FGF-8e, FGF-8f) and eight in mouse (FGF-8a-h).
• See the table below the pathway for additional information on the FGF-8 subfamily members including their suggested physiological functions and reported receptor binding specificities.
• FGF-9 subfamily members: FGF-9, FGF-16, and FGF-20.
• Lack a classical N-terminal signal peptide, but have an internal hydrophobic sequence that functions as a signal for their transport into the ER and secretion.
• Utilize heparin/HS as a co-factor to bind to FGF receptors.
• See the table below the pathway for additional information on the FGF-9 subfamily members including their suggested physiological functions and reported receptor binding specificities.
• FGF-11 subfamily members: FGF-11, FGF-12, FGF-13, and FGF-14.
• Also known as FGF homologous factors (FHFs), FGF-11 subfamily members have high sequence identity and structural homology with the FGF family, but are not secreted and do not activate FGF receptors.
• As intracellular FGFs, FGF-11 subfamily members interact with the cytosolic carboxy-terminal tail of voltage-gated sodium channels.
• See the table below the pathway for additional information on the FGF-11 subfamily members including their suggested physiological functions and reported receptor binding specificities.
• FGF-19 subfamily members: FGF-19 (human)/FGF-15 (mouse), FGF-21, and FGF-23.
• Bind to heparin/HS with very low affinity, facilitating their release from the ECM and their function as endocrine factors.
• Require Klotho proteins as co-factors to bind to FGF receptors.
• FGF-15 is the mouse orthologue of human FGF-19.
• See the table below the pathway for additional information on the FGF-19 subfamily members including their suggested physiological functions and reported receptor binding specificities.

Overview of Fibroblast Growth Factor (FGF) Family Signaling Pathways

The mammalian Fibroblast Growth Factor (FGF) superfamily consists of eighteen secreted proteins (FGF-1 – FGF-10 and FGF-16 – FGF-23) and four intracellular FGFs (FGF-11 – FGF-14), known as FGF homologous factors. The secreted FGFs belong to one of six subfamilies (FGF-1, FGF-4, FGF-7, FGF-8, FGF-9, and FGF-19) based on sequence homology, biological functions, and evolutionary relationships, while the intracellular FGFs make up the FGF-11 subfamily. Secreted FGFs are typically sequestered by heparan sulfate proteoglycans (HSPGs) that are tethered to the cell surface and/or associated with the extracellular matrix, causing their effects to be localized to nearby cells. Only the FGF-19 subfamily, including FGF-21, FGF-23, and FGF-19 in humans or the mouse FGF-19 equivalent, FGF-15, acts in an endocrine manner. Although these FGFs are also dependent on HSPGs for signaling, they bind to heparin/heparan sulfate (HS) with very low affinity compared to the other FGFs, allowing them to more freely circulate. Unlike the canonical, secreted FGFs, intracellular FGFs (iFGFs) are nonsignaling proteins that interact with the cytosolic carboxy-terminal tail of voltage-gated sodium (NaV) channels. This group of FGFs have been shown to regulate neuronal and myocardial excitability by modulating both the current density and gating properties of NaV channels.

Secreted FGFs bind to one of four transmembrane receptors with intracellular tyrosine kinase domains (FGF R1, FGF R2, FGF R3, and FGF R4) in a 2:2:2 HSPG-FGF-FGF receptor ratio. Ligand binding specificity is determined by the differential expression patterns of the FGFs, FGF receptors, and glycosaminoglycan structures, different receptor binding capacities, the requirement for specific co-factors such as the Klotho family proteins, and alternative splicing of the FGF receptors that results in two different versions of the extracellular Ig-like domain III (b or c). Following HSPG-ligand-binding to the FGF receptor, the receptor homodimerizes, leading to activation of the cytoplasmic intracellular kinase domain of the receptor, and recruitment and docking of adaptor proteins such as FRS2, GRB2, Shb, and Shc. These adaptor proteins subsequently activate multiple downstream signaling pathways including the Ras-MAPK pathway, the Jak-STAT pathway, the PI 3-Kinase-Akt pathway, the PLC gamma pathway, and the p38 and JNK MAPK pathways. Through these signaling pathways, FGFs promote fundamental cellular processes such as survival, proliferation, differentiation, and motility. Secreted FGFs have been shown to be involved in a wide range of biological processes during normal physiological development including cell differentiation in the early embryo, pattern formation, branching morphogenesis, limb development, and organogenesis, including heart and brain development. Additionally, they contribute to the maintenance of tissue homeostasis, repair, and metabolism in adult organisms. Gain or loss of function mutations in FGFs are associated with a variety of developmental defects and pathological conditions including cancer.

To learn more, please visit our FGF Family Research Area page

Subfamily Human Ligands Alternate Name Physiological Function (Based on the knockout mouse phenotype) Pathologies Associated with FGF Mutations Reported Receptor Binding Specificity
R1b R1c R2b R2c R3b R3c R4
FGF-1 FGF-1 FGF acidic; HBGF-1 Not established • FGF1 amplification - ovarian cancer X X X X X X X
FGF-2 FGF basic; HBGF-2 Wound healing • FGF2 overexpression - bladder cancer, prostate cancer, small cell lung carcinoma, hepatocellular carcinoma, melanoma X X   X   X X
Subfamily Human Ligands Alternate Name Physiological Function (Based on the knockout mouse phenotype) Pathologies Associated with FGF Mutations Reported Receptor Binding Specificity
R1b R1c R2b R2c R3b R3c R4
FGF-4 FGF-4 K-FGF; HBGF-4; HST-1 Limb bud and
heart development
• FGF4 amplication - breast cancer   X   X   X X
FGF-5 HBGF-5 Hair follicle
development and
growth cycle regulation
• FGF5 overexpression - glioblastoma   X   X   X  
FGF-6 HBGF-6; HST-2 Muscle development
and regeneration
• FGF6 overexpression - prostate cancer   X   X   X X
Subfamily Human Ligands Alternate Name Physiological Function (Based on the knockout mouse phenotype) Pathologies Associated with FGF Mutations Reported Receptor Binding Specificity
R1b R1c R2b R2c R3b R3c R4
FGF-7 FGF-3 HBGF-3; INT2 Inner ear development • FGF3 haploinsufficiency - Otodental syndrome
• FGF3 missense/frameshift mutation - Michel aplasia, LAMM syndrome
• FGF3 amplification - breast cancer
X   X        
FGF-7 KGF; HBGF-7 Branching morphogenesis • FGF7 polymorphism - COPD
• FGF7 overexpression - lung adenocarcinoma
  X    
FGF-10 KGF-2 Branching morphogenesis; Inner ear development • FGF10 nonsense mutation - Aplasia of the lacrimal and salivary glands (ALSG), Lacrimo-auriculo-dento-digital (LADD) syndrome
• FGF10 polymorphism - severe myopia
• FGF10 overexpression - breast cancer, prostate cancer
X X    
FGF-22   Presynapitc neural organizer   X   X        
Subfamily Human Ligands Alternate Name Physiological Function (Based on the knockout mouse phenotype) Pathologies Associated with FGF Mutations Reported Receptor Binding Specificity
R1b R1c R2b R2c R3b R3c R4
FGF-8 FGF-8a AIGF; HBGF-8 Brain, eye, ear, heart, kidney, and limb bud development • FGF8 nonsense mutation - Familial hypogonadotropic hypogonadism                          
• FGF8 missense mutation - cleft lip and palate, holoprosencephaly, craniofacial defects, hypothalamo-pituitary dysfunction
             
FGF-8b AIGF; HBGF-8   X   X   X X
FGF-8e AIGF; HBGF-8       X X
FGF-8f AIGF; HBGF-8     X   X X
FGF-17 FGF-13 Brain development • FGF17 missense mutation - Familial hypogonadotropic hypogonadism
• FGF17 overexpression - hepatocellular carcinoma, prostate cancer
  X   X   X X
FGF-18 ZFGF5 Bone development; Lung alveolar development • FGF18 polymorphism - nonsyndromic cleft lip and palate
• FGF18 overexpression - hepatocellular carcinoma
          X X
Subfamily Human Ligands Alternate Name Physiological Function (Based on the knockout mouse phenotype) Pathologies Associated with FGF Mutations Reported Receptor Binding Specificity
R1b R1c R2b R2c R3b R3c R4
FGF-9 FGF-9 GAF; HBGF-9 Organogenesis; Gonad development; Inner ear development • FGF9 missense mutation - Multiple synostosis syndrome (SYNS)                                 
• FGF9 promoter mutation - Sertoli cell-only syndrome (SCOS)                                 
• FGF9 frameshift/missense/nonsense mutations - colorectal cancer, endometrial cancer
• FGF9 overexpression - non-small cell lung cancer
  X   X X X X
FGF-16 MF4 Heart development • FGF16 nonsense mutation - metacarpal 4-5 fusion
• FGF16 overexpression - ovarian cancer
    X X X X
FGF-20 RHDA2 Neurotrophic factor • FGF20 polymorphism - risk of Parkinson's disease
• FGF20 frameshift mutation - bilateral renal agenesis
  X X X X X X
Subfamily Human Ligands Alternate Name Physiological Function (Based on the knockout mouse phenotype) Pathologies Associated with FGF Mutations Reported Receptor Binding Specificity
R1b R1c R2b R2c R3b R3c R4
FGF-11 FGF-11 FHF-3                  
  FGF-12 FHF-1   • FGF12 missense mutation - Brugada syndrome        
  FGF-13 FHF-2 Neuronal migration; Learning and memory • FGF13 nonsense mutation - Borjeson-Forssman-Lehmann syndrome (BFLS)
• Low FGF13 expression - X-linked congenital generalized hypertrichosis
       
  FGF-14 FHF-4 Neuronal firing; Movement and coordination; Learning and memory • FGF14 missense/deletion/translocation mutations - Spinocerebellar ataxia 27 (SCA27)              
Subfamily Human Ligands Alternate Name Physiological Function (Based on the knockout mouse phenotype) Pathologies Associated with FGF Mutations Reported Receptor Binding Specificity
R1b R1c R2b R2c R3b R3c R4
FGF-19 FGF-19  FGF-15 (mouse) Bile acid metabolism; lipolysis; gall bladder filling • FGF19 overexpression - prostate cancer, hepatocellular carcinoma   X   X   X X
  FGF-21 Energy/lipid metabolism • FGF21 polymorphism - increased risk of obesity and type 2 diabetes   X   X   X X
  FGF-23 ADHR; HPDR2; HYPF Phosphate and vitamin D homeostasis; Middle ear development • FGF23 missense mutation - Autosomal dominant hypophosphatemic rickets (ADHR), Familial tumoral calcinosis (FTC)
• FGF23 polymorphism - cardiac abnormalities in Kawasaki syndrome, increased risk of prostate cancer
  X   X   X X