P31371 (FGF9_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Fibroblast growth factor 9
Short name=FGF-9

Alternative name(s):
Glia-activating factor
Short name=GAF
Heparin-binding growth factor 9
Short name=HBGF-9

Gene names

Name:

FGF9

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	208 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Plays an important role in the regulation of embryonic development, cell proliferation, cell differentiation and cell migration. May have a role in glial cell growth and differentiation during development, gliosis during repair and regeneration of brain tissue after damage, differentiation and survival of neuronal cells, and growth stimulation of glial tumors. Ref.8 Ref.9
Subunit structure	Monomer. Homodimer. Interacts with FGFR1, FGFR2, FGFR3 and FGFR4. Affinity between fibroblast growth factors (FGFs) and their receptors is increased by heparan sulfate glycosaminoglycans that function as coreceptors. Ref.8 Ref.9 Ref.11 Ref.12
Subcellular location	Secreted.
Tissue specificity	Glial cells.
Post-translational modification	Three molecular species were found (30 kDa, 29 kDa and 25 kDa), cleaved at Leu-4, Val-13 and Ser-34 respectively. The smaller ones might be products of proteolytic digestion. Furthermore, there may be a functional signal sequence in the 30 kDa species which is uncleavable in the secretion step. N-glycosylated.
Involvement in disease	Multiple synostoses syndrome 3 (SYNS3) [MIM:612961]: A bone disease characterized by multiple progressive joint fusions that commonly involve proximal interphalangeal, tarsal-carpal, humeroradial and cervical spine joints. Additional features can include progressive conductive deafness and facial dysmorphism. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.13
Miscellaneous	Biochemical analysis of the Asn-99 mutation reveals a significantly impaired FGF signaling, as evidenced by diminished activity of the MAPK1/MAPK2 pathway and decreases CTNNB1 and MYC expression when compared with wild-type protein. Binding of mutant protein to the receptor FGFR3 is severely impaired, although homodimerization of mutant to itself or wild-type is not detectably affected, providing a basis for the observed defective FGF9 signaling.
Sequence similarities	Belongs to the heparin-binding growth factors family.

Ontologies

Keywords
Biological process	Differentiation
Cellular component	Secreted
Coding sequence diversity	Polymorphism
Disease	Deafness Disease mutation
Ligand	Heparin-binding
Molecular function	Developmental protein Growth factor Mitogen
PTM	Glycoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	angiogenesis Inferred from electronic annotation. Source: Compara cell-cell signaling Traceable author statement PubMed 8575785. Source: ProtInc chondrocyte differentiation Inferred from electronic annotation. Source: Compara embryonic digestive tract development Inferred from electronic annotation. Source: Compara embryonic limb morphogenesis Inferred from electronic annotation. Source: Compara embryonic skeletal system development Inferred from electronic annotation. Source: Compara epidermal growth factor receptor signaling pathway Traceable author statement. Source: Reactome fibroblast growth factor receptor signaling pathway Inferred from genetic interaction Ref.8. Source: MGI innate immune response Traceable author statement. Source: Reactome inner ear morphogenesis Inferred from electronic annotation. Source: Compara insulin receptor signaling pathway Traceable author statement. Source: Reactome lung-associated mesenchyme development Inferred from electronic annotation. Source: Compara male gonad development Inferred from expression pattern PubMed 17848411. Source: UniProtKB male sex determination Inferred from electronic annotation. Source: Compara negative regulation of Wnt receptor signaling pathway Inferred from electronic annotation. Source: Compara neurotrophin TRK receptor signaling pathway Traceable author statement. Source: Reactome osteoblast differentiation Inferred from electronic annotation. Source: Compara phosphatidylinositol-mediated signaling Traceable author statement. Source: Reactome positive regulation of MAPK cascade Inferred from electronic annotation. Source: Compara positive regulation of canonical Wnt receptor signaling pathway Inferred from electronic annotation. Source: Compara positive regulation of cardiac muscle cell proliferation Inferred from electronic annotation. Source: Compara positive regulation of cell division Inferred from electronic annotation. Source: UniProtKB-KW positive regulation of cell proliferation Inferred from direct assay Ref.1. Source: MGI positive regulation of epithelial cell proliferation Inferred from electronic annotation. Source: Compara positive regulation of gene expression Inferred from electronic annotation. Source: Compara positive regulation of mesenchymal cell proliferation Inferred from electronic annotation. Source: Compara positive regulation of smoothened signaling pathway Inferred from electronic annotation. Source: Compara positive regulation of vascular endothelial growth factor receptor signaling pathway Inferred from electronic annotation. Source: Compara protein import into nucleus Inferred from electronic annotation. Source: Compara regulation of timing of cell differentiation Inferred from electronic annotation. Source: Compara
Cellular_component	basement membrane Inferred from electronic annotation. Source: Compara cytoplasm Inferred from electronic annotation. Source: Compara extracellular space Inferred from direct assay Ref.1. Source: MGI
Molecular_function	growth factor activity Traceable author statement Ref.1. Source: ProtInc heparin binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Propeptide

1 – 3

3

PRO_0000008973

Chain

4 – 208

205

Fibroblast growth factor 9

PRO_0000008974

Amino acid modifications

Glycosylation

79

1

N-linked (GlcNAc...)

Natural variations

Natural variant

94

1

I → V. Ref.2
Corresponds to variant rs12427696 [ dbSNP | Ensembl ].

VAR_020944

Natural variant

99

1

S → N in SYNS3; expressed and secreted as efficiently as wild-type; however it induces compromised chondrocyte proliferation and differentiation accompanied by enhanced osteogenic differentiation and matrix mineralization of bone marrow-derived mesenchymal stem cells. Ref.13

VAR_063254

Experimental info

Sequence conflict

24 – 26

3

VLP → SLL AA sequence Ref.7

Sequence conflict

34

1

S → A AA sequence Ref.7

Secondary structure

1

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208

Helix Strand Turn

Details...

Helix

53 – 60

8

Beta strand

63 – 68

6

Beta strand

73 – 76

4

Beta strand

82 – 87

6

Helix

91 – 93

3

Beta strand

95 – 101

7

Beta strand

104 – 109

6

Turn

110 – 112

3

Beta strand

115 – 118

4

Beta strand

124 – 129

6

Helix

132 – 134

3

Beta strand

136 – 142

7

Beta strand

145 – 154

10

Turn

156 – 158

3

Beta strand

161 – 163

3

Helix

175 – 177

3

Helix

183 – 185

3

Beta strand

187 – 190

4

Helix

194 – 196

3

Helix

200 – 203

4

Sequences

	Sequence		Length	Mass (Da)
	P31371 [UniParc]. Last modified October 1, 1994. Version 3. Checksum: F32A0E7106EF59C9	FASTA	208	23,441
	10 20 30 40 50 60 MAPLGEVGNY FGVQDAVPFG NVPVLPVDSP VLLSDHLGQS EAGGLPRGPA VTDLDHLKGI 70 80 90 100 110 120 LRRRQLYCRT GFHLEIFPNG TIQGTRKDHS RFGILEFISI AVGLVSIRGV DSGLYLGMNE 130 140 150 160 170 180 KGELYGSEKL TQECVFREQF EENWYNTYSS NLYKHVDTGR RYYVALNKDG TPREGTRTKR 190 200 HQKFTHFLPR PVDPDKVPEL YKDILSQS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Molecular cloning of a novel cytokine cDNA encoding the ninth member of the fibroblast growth factor family, which has a unique secretion property." Miyamoto M., Naruo K., Seko C., Matsumoto S., Kondo T., Kurokawa T. Mol. Cell. Biol. 13:4251-4259(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Foreskin.
[2]	NIEHS SNPs program Submitted (JUL-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT VAL-94.
[3]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Kidney.
[4]	"The DNA sequence and analysis of human chromosome 13." Dunham A., Matthews L.H., Burton J., Ashurst J.L., Howe K.L., Ashcroft K.J., Beare D.M., Burford D.C., Hunt S.E., Griffiths-Jones S., Jones M.C., Keenan S.J., Oliver K., Scott C.E., Ainscough R., Almeida J.P., Ambrose K.D., Andrews D.T. , Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Bannerjee R., Barlow K.F., Bates K., Beasley H., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y., Burrill W., Carder C., Carter N.P., Chapman J.C., Clamp M.E., Clark S.Y., Clarke G., Clee C.M., Clegg S.C., Cobley V., Collins J.E., Corby N., Coville G.J., Deloukas P., Dhami P., Dunham I., Dunn M., Earthrowl M.E., Ellington A.G., Faulkner L., Frankish A.G., Frankland J., French L., Garner P., Garnett J., Gilbert J.G.R., Gilson C.J., Ghori J., Grafham D.V., Gribble S.M., Griffiths C., Hall R.E., Hammond S., Harley J.L., Hart E.A., Heath P.D., Howden P.J., Huckle E.J., Hunt P.J., Hunt A.R., Johnson C., Johnson D., Kay M., Kimberley A.M., King A., Laird G.K., Langford C.J., Lawlor S., Leongamornlert D.A., Lloyd D.M., Lloyd C., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., McLaren S.J., McMurray A., Milne S., Moore M.J.F., Nickerson T., Palmer S.A., Pearce A.V., Peck A.I., Pelan S., Phillimore B., Porter K.M., Rice C.M., Searle S., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., Steward C.A., Sycamore N., Tester J., Thomas D.W., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., Whitehead S.L., Willey D.L., Wilming L., Wray P.W., Wright M.W., Young L., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Beck S., Bentley D.R., Rogers J., Ross M.T. Nature 428:522-528(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[7]	"Novel secretory heparin-binding factors from human glioma cells (glia-activating factors) involved in glial cell growth. Purification and biological properties." Naruo K., Seko C., Kuroshima K., Matsutani E., Sasada R., Kondo T., Kurokawa T. J. Biol. Chem. 268:2857-2864(1993) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 4-26 AND 34-54. Tissue: Glial tumor.
[8]	"Receptor specificity of the fibroblast growth factor family." Ornitz D.M., Xu J., Colvin J.S., McEwen D.G., MacArthur C.A., Coulier F., Gao G., Goldfarb M. J. Biol. Chem. 271:15292-15297(1996) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH FGFR2 AND FGFR3, FUNCTION IN CELL PROLIFERATION.
[9]	"Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family." Zhang X., Ibrahimi O.A., Olsen S.K., Umemori H., Mohammadi M., Ornitz D.M. J. Biol. Chem. 281:15694-15700(2006) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH FGFR1; FGFR2; FGFR3 AND FGFR4, FUNCTION IN STIMULATION OF CELL PROLIFERATION.
[10]	"Fibroblast growth factor signalling: from development to cancer." Turner N., Grose R. Nat. Rev. Cancer 10:116-129(2010) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW.
[11]	"Structure of fibroblast growth factor 9 shows a symmetric dimer with unique receptor- and heparin-binding interfaces." Hecht H.J., Adar R., Hofmann B., Bogin O., Weich H., Yayon A. Acta Crystallogr. D 57:378-384(2001) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS), SUBUNIT, HEPARIN-BINDING.
[12]	"Crystal structure of fibroblast growth factor 9 reveals regions implicated in dimerization and autoinhibition." Plotnikov A.N., Eliseenkova A.V., Ibrahimi O.A., Shriver Z., Sasisekharan R., Lemmon M.A., Mohammadi M. J. Biol. Chem. 276:4322-4329(2001) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 35-208, SUBUNIT.
[13]	"Multiple synostoses syndrome is due to a missense mutation in exon 2 of FGF9 gene." Wu X.L., Gu M.M., Huang L., Liu X.S., Zhang H.X., Ding X.Y., Xu J.Q., Cui B., Wang L., Lu S.Y., Chen X.Y., Zhang H.G., Huang W., Yuan W.T., Yang J.M., Gu Q., Fei J., Chen Z., Yuan Z.M., Wang Z.G. Am. J. Hum. Genet. 85:53-63(2009) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT SYNS3 ASN-99, CHARACTERIZATION OF VARIANT SYNS3 ASN-99.
+	Additional computationally mapped references.

Web resources

R&D Systems' cytokine source book: FGF-9

NIEHS-SNPs

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

D14838 mRNA. Translation: BAA03572.1.
AY682094 Genomic DNA. Translation: AAT74624.1.
AK290792 mRNA. Translation: BAF83481.1.
AL139378 Genomic DNA. Translation: CAC17692.1.
CH471075 Genomic DNA. Translation: EAX08316.1.
BC069692 mRNA. Translation: AAH69692.1.
BC103978 mRNA. Translation: AAI03979.1.
BC103979 mRNA. Translation: AAI03980.1.

IPI

IPI00011172.

PIR

A48137.

RefSeq

NP_002001.1. NM_002010.2.

UniGene

Hs.111.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1G82	X-ray	2.60	A/B/C/D	49-208	[»]
1IHK	X-ray	2.20	A	35-208	[»]

ProteinModelPortal

P31371.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-6036N.

STRING

9606.ENSP00000371790.

PTM databases

PhosphoSite

P31371.

Polymorphism databases

DMDM

544290.

Proteomic databases

PaxDb

P31371.

PRIDE

P31371.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000382353; ENSP00000371790; ENSG00000102678.

GeneID

2254.

KEGG

hsa:2254.

UCSC

uc001uog.2. human.

Organism-specific databases

CTD

2254.

GeneCards

GC13P022245.

HGNC

HGNC:3687. FGF9.

HPA

CAB004392.

MIM

600921. gene.
612961. phenotype.

neXtProt

NX_P31371.

Orphanet

3237. Multiple synostoses syndrome.

PharmGKB

PA28126.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG269410.

HOGENOM

HOG000236341.

HOVERGEN

HBG007580.

InParanoid

P31371.

KO

K04358.

OMA

GTKSRRH.

OrthoDB

EOG46WZ9V.

PhylomeDB

P31371.

Enzyme and pathway databases

Pathway_Interaction_DB

fgf_pathway. FGF signaling pathway.

Reactome

REACT_111102. Signal Transduction.
REACT_116125. Disease.
REACT_6900. Immune System.

SignaLink

P31371.

Gene expression databases

Bgee

P31371.

CleanEx

HS_FGF9.

Genevestigator

P31371.

GermOnline

ENSG00000102678. Homo sapiens.

Family and domain databases

InterPro

IPR008996. Cytokine_IL1-like.
IPR002209. GF_heparin-bd.
IPR002348. IL1_HBGF.
[Graphical view]

PANTHER

PTHR11486. PTHR11486. 1 hit.

Pfam

PF00167. FGF. 1 hit.
[Graphical view]

PRINTS

PR00263. HBGFFGF.
PR00262. IL1HBGF.

SMART

SM00442. FGF. 1 hit.
[Graphical view]

SUPFAM

SSF50353. Cytok_IL1_like. 1 hit.

PROSITE

PS00247. HBGF_FGF. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

EvolutionaryTrace

P31371.

GenomeRNAi

2254.

NextBio

9131.

SOURCE

Search...

Entry information

Entry name

FGF9_HUMAN

Accession

Primary (citable) accession number: P31371
Secondary accession number(s): A8K427, Q3SY32

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 1, 1993
Last sequence update:	October 1, 1994
Last modified:	May 29, 2013
This is version 144 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.