FGF6

Summary

FGF6 (fibroblast growth factor 6, HGNC:3684) is a protein-coding gene on chromosome 12p13.32, encoding Fibroblast growth factor 6 (P10767). Plays an important role in the regulation of cell proliferation, cell differentiation, angiogenesis and myogenesis, and is required for normal muscle regeneration.

The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities, and are involved in a variety of biological processes, including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. This gene displayed oncogenic transforming activity when transfected into mammalian cells. The mouse homolog of this gene exhibits a restricted expression profile predominantly in the myogenic lineage, which suggested a role in muscle regeneration or differentiation.

Source: NCBI Gene 2251 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 33 total
• MANE Select transcript: NM_020996

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3684
Approved symbol	FGF6
Name	fibroblast growth factor 6
Location	12p13.32
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000111241
Ensembl biotype	protein_coding
OMIM	134921
Entrez	2251

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000228837, ENST00000535390, ENST00000543077

RefSeq mRNA: 1 — MANE Select: NM_020996 NM_020996

CCDS: CCDS8527

Canonical transcript exons

ENST00000228837 — 3 exons

Exon	Start	End
ENSE00000713899	4444133	4444236
ENSE00000802846	4434142	4434391
ENSE00000802847	4445225	4445815

Expression profiles

Bgee: expression breadth broad, 60 present calls, max score 90.90.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0879 / max 18.9165, expressed in 22 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
129019	0.0879	22

Top tissues by expression

238 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
type B pancreatic cell	CL:0000169	90.90	silver quality
olfactory bulb	UBERON:0002264	88.91	gold quality
hindlimb stylopod muscle	UBERON:0004252	83.84	gold quality
triceps brachii	UBERON:0001509	81.74	silver quality
diaphragm	UBERON:0001103	81.09	gold quality
gluteal muscle	UBERON:0002000	79.46	silver quality
gastrocnemius	UBERON:0001388	77.05	gold quality
muscle of leg	UBERON:0001383	76.71	gold quality
muscle organ	UBERON:0001630	76.53	gold quality
cervix squamous epithelium	UBERON:0006922	75.42	gold quality
skeletal muscle tissue	UBERON:0001134	74.74	gold quality
nasal cavity epithelium	UBERON:0005384	74.59	gold quality
oocyte	CL:0000023	74.54	silver quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	73.87	gold quality
cervix epithelium	UBERON:0004801	72.91	gold quality
Brodmann (1909) area 46	UBERON:0006483	72.55	gold quality
vena cava	UBERON:0004087	72.30	gold quality
myocardium	UBERON:0002349	72.23	gold quality
thymus	UBERON:0002370	72.04	gold quality
pancreatic ductal cell	CL:0002079	72.02	silver quality
muscle tissue	UBERON:0002385	71.61	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	71.47	gold quality
parotid gland	UBERON:0001831	71.39	gold quality
left ventricle myocardium	UBERON:0006566	71.25	gold quality
cardiac muscle of right atrium	UBERON:0003379	70.99	gold quality
hair follicle	UBERON:0002073	70.53	gold quality
lateral globus pallidus	UBERON:0002476	70.32	silver quality
cardia of stomach	UBERON:0001162	70.25	gold quality
CA1 field of hippocampus	UBERON:0003881	69.90	gold quality
body of tongue	UBERON:0011876	68.00	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.13

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): RBPJ

Literature-anchored findings (GeneRIF, showing 8)

• FGF6 exhibits antitumor activity in vitro and correlates with expression of FGF receptors in medulloblastoma cells (PMID:11801566)
• These data demonstrate that FGF-6 may be considered a regulator of bone metabolism as shown by its activity on both osteoblasts and osteoclasts. (PMID:20458746)
• FGF6 downregulation correlated with iron-metabolism dysfunction in systemic sclerosis and cancer. (PMID:30814063)
• Skeletal muscle-targeted delivery of Fgf6 protects mice from diet-induced obesity and insulin resistance. (PMID:34491915)
• LINC00265 promotes the viability, proliferation, and migration of bladder cancer cells via the miR-4677-3p/FGF6 axis. (PMID:34591706)
• FGF6 promotes cardiac repair after myocardial infarction by inhibiting the Hippo pathway. (PMID:35355356)
• Reprint of: Fibroblast Growth Factor 6. (PMID:39214748)
• FGF6 inhibits oral squamous cell carcinoma progression by regulating PI3K/AKT and MAPK pathways. (PMID:39506091)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	fgf6a	ENSDARG00000009351
danio_rerio	fgf6b	ENSDARG00000045856
mus_musculus	Fgf6	ENSMUSG00000000183
rattus_norvegicus	Fgf6	ENSRNOG00000084144

Paralogs (21): FGF10 (ENSG00000070193), FGF22 (ENSG00000070388), FGF4 (ENSG00000075388), FGF20 (ENSG00000078579), FGF14 (ENSG00000102466), FGF9 (ENSG00000102678), FGF21 (ENSG00000105550), FGF8 (ENSG00000107831), FGF1 (ENSG00000113578), FGF12 (ENSG00000114279), FGF23 (ENSG00000118972), FGF13 (ENSG00000129682), FGF5 (ENSG00000138675), FGF2 (ENSG00000138685), FGF7 (ENSG00000140285), FGF18 (ENSG00000156427), FGF17 (ENSG00000158815), FGF11 (ENSG00000161958), FGF19 (ENSG00000162344), FGF3 (ENSG00000186895), FGF16 (ENSG00000196468)

Protein

Protein identifiers

Fibroblast growth factor 6 — P10767 (reviewed: P10767)

Alternative names: Heparin secretory-transforming protein 2, Heparin-binding growth factor 6

All UniProt accessions (3): P10767, A0A7U3JW05, H0YGZ9

UniProt curated annotations — full annotation on UniProt →

Function. Plays an important role in the regulation of cell proliferation, cell differentiation, angiogenesis and myogenesis, and is required for normal muscle regeneration.

Subunit / interactions. Interacts with FGFR1, FGFR2 and FGFR4. Affinity between fibroblast growth factors (FGFs) and their receptors is increased by heparan sulfate glycosaminoglycans that function as coreceptors.

Subcellular location. Secreted. Extracellular space.

Tissue specificity. Leukemia cell lines with platelet/ megakaryocytic differentiation potential.

Similarity. Belongs to the heparin-binding growth factors family.

RefSeq proteins (1): NP_066276* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002209	Fibroblast_GF_fam	Family
IPR008996	IL1/FGF	Homologous_superfamily

Pfam: PF00167

UniProt features (9 total): sequence variant 4, signal peptide 1, chain 1, glycosylation site 1, disulfide bond 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P10767-F1	79.20	0.62

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (1): 90–157

Glycosylation sites (1): 45

Function

Pathways and Gene Ontology

Reactome pathways

28 pathways

ID	Pathway
R-HSA-109704	PI3K Cascade
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-1839122	Signaling by activated point mutants of FGFR1
R-HSA-190322	FGFR4 ligand binding and activation
R-HSA-190373	FGFR1c ligand binding and activation
R-HSA-190375	FGFR2c ligand binding and activation
R-HSA-2033519	Activated point mutants of FGFR2
R-HSA-2219530	Constitutive Signaling by Aberrant PI3K in Cancer
R-HSA-5654219	Phospholipase C-mediated cascade: FGFR1
R-HSA-5654221	Phospholipase C-mediated cascade; FGFR2
R-HSA-5654228	Phospholipase C-mediated cascade; FGFR4
R-HSA-5654687	Downstream signaling of activated FGFR1
R-HSA-5654688	SHC-mediated cascade:FGFR1
R-HSA-5654689	PI-3K cascade:FGFR1
R-HSA-5654693	FRS-mediated FGFR1 signaling
R-HSA-5654695	PI-3K cascade:FGFR2
R-HSA-5654699	SHC-mediated cascade:FGFR2
R-HSA-5654700	FRS-mediated FGFR2 signaling
R-HSA-5654712	FRS-mediated FGFR4 signaling
R-HSA-5654719	SHC-mediated cascade:FGFR4
R-HSA-5654720	PI-3K cascade:FGFR4
R-HSA-5654726	Negative regulation of FGFR1 signaling
R-HSA-5654727	Negative regulation of FGFR2 signaling
R-HSA-5654733	Negative regulation of FGFR4 signaling
R-HSA-5655253	Signaling by FGFR2 in disease
R-HSA-5655302	Signaling by FGFR1 in disease
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling

MSigDB gene sets: 211 (showing top): ATF_B, FXR_IR1_Q6, REACTOME_SIGNALING_BY_INSULIN_RECEPTOR, PAX4_01, GOBP_CARTILAGE_DEVELOPMENT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, KEGG_MAPK_SIGNALING_PATHWAY, REACTOME_FGFR2C_LIGAND_BINDING_AND_ACTIVATION, MODULE_64, REACTOME_SIGNALING_BY_FGFR, REACTOME_FGFR1_LIGAND_BINDING_AND_ACTIVATION, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_NEUROGENESIS, CREBP1_Q2, GOMF_GROWTH_FACTOR_ACTIVITY

GO Biological Process (11): cartilage condensation (GO:0001502), angiogenesis (GO:0001525), positive regulation of cell population proliferation (GO:0008284), fibroblast growth factor receptor signaling pathway (GO:0008543), neurogenesis (GO:0022008), regulation of cell migration (GO:0030334), positive regulation of MAPK cascade (GO:0043410), myoblast differentiation (GO:0045445), positive regulation of cell division (GO:0051781), signal transduction (GO:0007165), cell differentiation (GO:0030154)

GO Molecular Function (3): fibroblast growth factor receptor binding (GO:0005104), growth factor activity (GO:0008083), protein binding (GO:0005515)

GO Cellular Component (5): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737), sarcolemma (GO:0042383), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
Downstream signaling of activated FGFR1	4
Downstream signaling of activated FGFR2	4
Downstream signaling of activated FGFR4	3
IRS-mediated signalling	1
Intracellular signaling by second messengers	1
FGFR1 mutant receptor activation	1
Signaling by FGFR4	1
FGFR1 ligand binding and activation	1
FGFR2 ligand binding and activation	1
FGFR2 mutant receptor activation	1
PI3K/AKT Signaling in Cancer	1
Signaling by FGFR1	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
positive regulation of cellular process	2
cell differentiation	2
skeletal system morphogenesis	1
cartilage development	1
cell aggregation	1
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
cell population proliferation	1
regulation of cell population proliferation	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cellular response to fibroblast growth factor stimulus	1
nervous system development	1
cell migration	1
regulation of cell motility	1
MAPK cascade	1
regulation of MAPK cascade	1
positive regulation of intracellular signal transduction	1
muscle structure development	1
cell division	1
regulation of cell division	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cellular developmental process	1
growth factor receptor binding	1
receptor ligand activity	1
binding	1
intracellular anatomical structure	1
plasma membrane	1

Protein interactions and networks

STRING

3582 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FGF6	FGFR1	P11362	997
FGF6	FGFR4	P22455	993
FGF6	EGF	P01133	989
FGF6	KL	Q9UEF7	986
FGF6	FGFR2	P18443	968
FGF6	HSPG2	P98160	948
FGF6	FGFBP1	Q14512	942
FGF6	DCN	P07585	936
FGF6	CDH2	P19022	879
FGF6	FGFR3	P22607	879
FGF6	HGF	P14210	876
FGF6	CD44	P16070	874
FGF6	KLB	Q86Z14	844
FGF6	FRS2	Q8WU20	838
FGF6	TGFB1	P01137	824

IntAct

28 interactions, top by confidence:

A	B	Type	Score
NCALD	FGF6	psi-mi:“MI:0915”(physical association)	0.560
FGF6	NCALD	psi-mi:“MI:0915”(physical association)	0.560
	FGF6	psi-mi:“MI:0407”(direct interaction)	0.440
FGFR1	FGF6	psi-mi:“MI:0407”(direct interaction)	0.440
KRT35	TIMP1	psi-mi:“MI:0914”(association)	0.350
BRAF	FGF6	psi-mi:“MI:2364”(proximity)	0.270
FBXW7	FGF6	psi-mi:“MI:2364”(proximity)	0.270
SMAD4	FGF6	psi-mi:“MI:2364”(proximity)	0.270
FGF6	SMARCA4	psi-mi:“MI:2364”(proximity)	0.270
SMARCA4	FGF6	psi-mi:“MI:2364”(proximity)	0.270
SPOP	FGF6	psi-mi:“MI:2364”(proximity)	0.270
FGF6	SPOP	psi-mi:“MI:2364”(proximity)	0.270
EGFR	FGF6	psi-mi:“MI:2364”(proximity)	0.270
FGF6	PTPN11	psi-mi:“MI:2364”(proximity)	0.270
FGF6	PTEN	psi-mi:“MI:2364”(proximity)	0.270
FGF6	AKT1	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (5): FGF6 (Protein-peptide), FGF6 (Protein-peptide), FGF6 (Two-hybrid), FGF6 (Affinity Capture-MS), FGF6 (Affinity Capture-RNA)

ESM2 similar proteins: B0LPN4, E9PZQ0, E9Q401, F1LMY4, O14926, O18728, O95834, P10767, P11403, P11716, P16960, P21658, P21817, P30957, P47823, P55075, P85845, Q13144, Q16658, Q24498, Q24524, Q32M02, Q3U7R1, Q4R4H3, Q5CZL1, Q5E9M9, Q5XGM5, Q61553, Q64350, Q6P6T4, Q6P9Z4, Q6PFQ7, Q6SZW1, Q7TNG5, Q7TSA0, Q7Z6L1, Q8CHW4, Q8IXI1, Q8JZN7, Q8K2J0

Diamond homologs: A0MTF4, A6P7H6, M3X9S6, O15520, O35565, O43320, O54769, P03968, P03969, P05230, P05524, P08620, P09038, P10767, P11403, P11487, P12034, P12226, P13109, P15655, P15656, P19596, P20002, P20003, P21658, P21781, P31371, P34004, P36363, P36364, P36386, P48798, P48799, P48800, P48801, P48802, P48803, P48804, P48805, P48806

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
FGF6	up-regulates	FGFR4	binding
FGF6	up-regulates	FGFR2	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

33 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	29
Likely benign	3
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

547 predictions. Top by Δscore:

Variant	Effect	Δscore
12:4445221:TCACT:T	donor_loss	1.0000
12:4445222:CA:C	donor_loss	1.0000
12:4445223:A:AC	donor_gain	1.0000
12:4445223:ACTG:A	donor_loss	1.0000
12:4445224:C:CA	donor_gain	1.0000
12:4445224:CT:C	donor_gain	1.0000
12:4445224:CTGT:C	donor_gain	1.0000
12:4435561:A:C	acceptor_gain	0.9900
12:4444125:GAAC:G	donor_loss	0.9900
12:4444126:AACTC:A	donor_loss	0.9900
12:4444127:ACT:A	donor_loss	0.9900
12:4444128:C:CG	donor_loss	0.9900
12:4444129:TCACC:T	donor_loss	0.9900
12:4444130:CACCG:C	donor_loss	0.9900
12:4444233:AGGCC:A	acceptor_loss	0.9900
12:4444234:GGCC:G	acceptor_loss	0.9900
12:4444235:GCC:G	acceptor_loss	0.9900
12:4444236:CCTG:C	acceptor_loss	0.9900
12:4444237:C:A	acceptor_loss	0.9900
12:4444237:C:CC	acceptor_gain	0.9900
12:4444662:G:C	donor_gain	0.9900
12:4445218:CACT:C	donor_loss	0.9900
12:4445224:CTG:C	donor_gain	0.9900
12:4445224:CTGTA:C	donor_gain	0.9900
12:4434392:C:CC	acceptor_gain	0.9800
12:4434403:A:C	acceptor_gain	0.9800
12:4435554:C:CT	acceptor_gain	0.9800
12:4443334:T:TA	donor_gain	0.9800
12:4444124:TGAAC:T	donor_loss	0.9800
12:4444148:T:TA	donor_gain	0.9800

AlphaMissense

1326 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:4445283:A:C	F96L	0.999
12:4445283:A:T	F96L	0.999
12:4445285:A:G	F96L	0.999
12:4434366:A:G	F159S	0.998
12:4434230:G:C	F204L	0.997
12:4434230:G:T	F204L	0.997
12:4434231:A:G	F204S	0.997
12:4434232:A:G	F204L	0.997
12:4445301:G:C	C90W	0.997
12:4434366:A:C	F159C	0.996
12:4434282:C:A	G187V	0.995
12:4434282:C:T	G187E	0.995
12:4444169:G:C	F138L	0.995
12:4444169:G:T	F138L	0.995
12:4444171:A:G	F138L	0.995
12:4445302:C:T	C90Y	0.995
12:4434334:C:G	A170P	0.994
12:4445287:C:T	G95D	0.994
12:4434231:A:C	F204C	0.993
12:4434235:G:C	H203D	0.993
12:4434297:G:T	A182D	0.993
12:4434351:A:G	L164P	0.993
12:4434371:G:C	C157W	0.993
12:4444167:A:T	V139D	0.993
12:4445248:C:T	G108E	0.993
12:4445284:A:G	F96S	0.993
12:4434272:C:A	K190N	0.992
12:4434272:C:G	K190N	0.992
12:4434365:G:C	F159L	0.992
12:4434365:G:T	F159L	0.992

dbSNP variants (sampled 300 via entrez): RS1000138042 (12:4435383 T>C), RS1000283530 (12:4444036 A>C,G), RS1001113210 (12:4446186 A>G), RS1001302295 (12:4439421 G>A), RS1001366457 (12:4440738 A>G), RS1001737295 (12:4438636 C>T), RS1001842901 (12:4447278 A>G), RS1002104563 (12:4438848 C>A,G), RS1002720804 (12:4434059 G>A,T), RS1002797881 (12:4433776 T>A,C), RS1002809954 (12:4441660 C>T), RS1003149948 (12:4439780 A>G), RS1003515050 (12:4446956 A>G,T), RS1003626432 (12:4441387 G>A), RS1003914954 (12:4440098 A>T)

Disease associations

OMIM: gene MIM:134921 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST000703_5	Phosphorus levels	4.000000e-09
GCST001792_1	Colorectal cancer	3.000000e-08
GCST001792_2	Colorectal cancer	5.000000e-10
GCST002345_12	Response to cytadine analogues (cytosine arabinoside)	5.000000e-06
GCST003720_28	Migraine	2.000000e-17
GCST003721_6	Migraine without aura	3.000000e-09
GCST003986_4	Migraine	1.000000e-18
GCST005981_9	Phosphorus levels	3.000000e-18
GCST007939_1	Medication use (antimigraine preparations)	8.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004861	phosphorus measurement
EFO:0009939	Antimigraine preparation use measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
cordycepin	increases expression, increases secretion	1
CGP 52608	increases reaction, affects binding	1
Gefitinib	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Acetylcysteine	decreases reaction, increases expression, increases secretion	1
Adenosine	increases expression, increases secretion	1
Arsenic	affects expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cadmium	increases expression	1
Cannabinoids	affects methylation, increases abundance	1
Estradiol	increases expression	1
Malathion	increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Polycyclic Aromatic Hydrocarbons	increases expression	1
Cyclosporine	decreases methylation	1
Aflatoxin B1	decreases methylation	1
Cadmium Chloride	decreases reaction, increases expression, increases secretion	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.