[R&D Systems] FGF Family Signaling Pathways

▒ FGF Family Signaling Pathways

Fibroblast Growth Factor (FGF) Family Signaling Pathways

포유류의 Fibroblast Growth Factor (FGF) superfamily는 18개의 secreted proteins (FGF-1 – FGF-10 및 FGF-16 – FGF-23)와 FGF homologous factors로 알려진 4개의 intracellular FGFs (FGF-11 – FGF-14)로 구성됩니다.

Secreted FGFs는 서열 상동성(sequence homology), 생물학적 기능, 진화적 관계를 바탕으로 6개의 subfamilies (FGF-1, FGF-4, FGF-7, FGF-8, FGF-9, FGF-19) 중 하나에 속하며, intracellular FGFs는 FGF-11 subfamily를 형성합니다.

1. Secreted FGFs와 Intracellular FGFs (iFGFs)의 특성

Secreted FGFs (주변 분비 및 내분비)
- 일반적으로 세포 표면에 결합되어 있거나 extracellular matrix와 결합된 heparan sulfate proteoglycans (HSPGs)에 의해 격리(sequestered)되어 있어, 그 효과가 인접한 세포로 국소화됩니다.
- FGF-19 subfamily (FGF-19, FGF-21, FGF-23 / 마우스의 경우 FGF-15)만이 예외적으로 endocrine 방식으로 작용합니다. 이들은 시그널링을 위해 HSPGs에 의존하긴 하지만, 다른 FGF들에 비해 heparin/heparan sulfate (HS)에 대한 결합 친화도(affinity)가 매우 낮아 혈액을 통해 더 자유롭게 순환할 수 있습니다.

Intracellular FGFs (iFGFs, 세포 내 FGF)
- 일반적인 secreted FGFs와 달리, 시그널링을 직접 유도하지 않는 nonsignaling proteins입니다.
- Voltage-gated sodium ( $Na_V$ ) channels의 cytosolic carboxy-terminal tail과 상호작용합니다. 이 그룹은 $Na_V$ channels의 current density와 gating properties를 모두 조절함으로써 neuronal 및 myocardial excitability를 조절하는 것으로 밝혀졌습니다.

2. FGF Receptor 결합 및 Downstream Signaling

Secreted FGFs는 transmembrane receptors인 4개의 FGF receptors (FGF R1, FGF R2, FGF R3, FGF R4) 중 하나에 2:2:2 HSPG-FGF-FGF receptor ratio로 결합합니다.

결합 특이성(Specificity) 결정 요인:
- FGFs, FGF receptors, 그리고 glycosaminoglycan structures의 차별적인 발현 패턴.
- 서로 다른 receptor 결합 능력.
- Klotho family proteins와 같은 특정 co-factors의 필요성.
- FGF receptors의 alternative splicing으로 인해 extracellular Ig-like domain III의 두 가지 버전(b 또는 c) 생성.

Signaling Cascade

HSPG-ligand가 FGF receptor에 결합하면 receptor의 homodimerization이 유도됩니다. 이는 receptor의 cytoplasmic intracellular kinase domain 활성화로 이어지며, FRS2, GRB2, Shb, Shc와 같은 adaptor proteins의 recruitment 및 docking을 유도합니다.

이 adaptor proteins들은 결과적으로 다음과 같은 다양한 downstream signaling pathways를 활성화합니다:

Ras-MAPK pathway
Jak-STAT pathway
PI 3-Kinase-Akt pathway
PLC gamma pathway
p38 and JNK MAPK pathways

3. 생물학적 기능 및 임상적 의의

FGF는 이러한 시그널링 경로를 통해 세포의 survival, proliferation, differentiation, motility와 같은 근본적인 세포 프로세스를 촉진합니다.

Normal Physiological Development: 초기 배아(early embryo)의 cell differentiation, pattern formation, branching morphogenesis, limb development, 그리고 심장 및 뇌 발달을 포함한 organogenesis 등 광범위한 생물학적 과정에 관여합니다.
Adult Organisms: 성체 조직의 homeostasis 유지, repair, 그리고 metabolism에 기여합니다.
Pathological Conditions: FGF의 gain-of-function 또는 loss-of-function mutations는 다양한 발달 장애 및 cancer를 포함한 병리적 상태와 밀접하게 연관되어 있습니다.

Subfamily	Ligands	Alternate Name	Physiological Function (Based on the knockout mouse phenotype)	Pathologies Associated with FGF Mutations	Reported Receptor Binding Specificity
Subfamily	Ligands	Alternate Name		Pathologies Associated with FGF Mutations	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-1	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	Ligands	Alternate Name	Physiological Function (Based on the knockout mouse phenotype)	Pathologies Associated with FGF Mutations	Reported Receptor Binding Specificity
Subfamily	Ligands	Alternate Name		Pathologies Associated with FGF Mutations	R1b	R1c	R2b	R2c	R3b	R3c	R4
FGF-4	FGF-4	K-FGF; HBGF-4; HST-1	Limb bud and heart development	FGF4 amplification - 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	Ligands	Alternate Name	Physiological Function (Based on the knockout mouse phenotype)	Pathologies Associated with FGF Mutations	Reported Receptor Binding Specificity
Subfamily	Ligands	Alternate Name		Pathologies Associated with FGF Mutations	R1b	R1c	R2b	R2c	R3b	R3c	R4
FGF-7	FGF-3	HBGF-3	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		Presynaptic neural organizer		X		X
Subfamily	Ligands	Alternate Name	Physiological Function (Based on the knockout mouse phenotype)	Pathologies Associated with FGF Mutations	Reported Receptor Binding Specificity
Subfamily	Ligands	Alternate Name		Pathologies Associated with FGF Mutations	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	Ligands	Alternate Name	Physiological Function (Based on the knockout mouse phenotype)	Pathologies Associated with FGF Mutations	Reported Receptor Binding Specificity
Subfamily	Ligands	Alternate Name		Pathologies Associated with FGF Mutations	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 syn- drome (SCOS) • FGF9 frameshift or missense or nonsense muta- tions - colorectal cancer, endometrial cancer • FGF9 overexpression - NSCLC		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	Ligands	Alternate Name	Physiological Function (Based on the knockout mouse phenotype))	Pathologies Associated with FGF Mutations	Reported Receptor Binding Specificity
Subfamily	Ligands	Alternate Name		Pathologies Associated with FGF Mutations	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 or deletion or translocation mutations - Spinocerebellar ataxia 27 (SCA27)
Subfamily	Ligands	Alternate Name	Physiological Function (Based on the knockout mouse phenotype)	Pathologies Associated with FGF Mutations	Reported Receptor Binding Specificity
Subfamily	Ligands	Alternate Name		Pathologies Associated with FGF Mutations	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