Q9GZV9 (FGF23_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Fibroblast growth factor 23
Short name=FGF-23

Alternative name(s):
Phosphatonin
Tumor-derived hypophosphatemia-inducing factor

Cleaved into the following 2 chains:

1. Fibroblast growth factor 23 N-terminal peptide
2. Fibroblast growth factor 23 C-terminal peptide

Gene names

Name:	FGF23
Synonyms:	HYPF
ORF Names:	UNQ3027/PRO9828

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	251 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	Regulator of phosphate homeostasis. Inhibits renal tubular phosphate transport by reducing SLC34A1 levels. Upregulates EGR1 expression in the presence of KL By similarity. Acts directly on the parathyroid to decrease PTH secretion By similarity. Regulator of vitamin-D metabolism. Negatively regulates osteoblast differentiation and matrix mineralization. Ref.2 Ref.8 Ref.13 Ref.14 Ref.16
Subunit structure	Interacts with FGFR1, FGFR2, FGFR3 and FGFR4. Affinity between fibroblast growth factors (FGFs) and their receptors is increased by KL and heparan sulfate glycosaminoglycans that function as coreceptors By similarity. Ref.14
Subcellular location	Secreted. Note: Secretion is dependent on O-glycosylation. Ref.15
Tissue specificity	Expressed in osteogenic cells particularly during phases of active bone remodeling. In adult trabecular bone, expressed in osteocytes and flattened bone-lining cells (inactive osteoblasts). Ref.11
Post-translational modification	Following secretion this protein is inactivated by cleavage into a N-terminal fragment and a C-terminal fragment. The processing is effected by proprotein convertases. O-glycosylated by GALT3. Glycosylation is necessary for secretion; it blocks processing by proprotein convertases when the O-glycan is alpha 2,6-sialylated. Competition between proprotein convertase cleavage and block of cleavage by O-glycosylation determines the level of secreted active FGF23. Ref.15
Involvement in disease	Defects in FGF23 are the cause of autosomal dominant hypophosphataemic rickets (ADHR) [MIM:193100]. ADHR is characterized by low serum phosphorus concentrations, rickets, osteomalacia, leg deformities, short stature, bone pain and dental abscesses. Ref.2 Ref.8 Ref.15 Defects in FGF23 are a cause of hyperphosphatemic familial tumoral calcinosis (HFTC) [MIM:211900]. HFTC is a severe autosomal recessive metabolic disorder that manifests with hyperphosphatemia and massive calcium deposits in the skin and subcutaneous tissues. Ref.19
Sequence similarities	Belongs to the heparin-binding growth factors family.

Ontologies

Keywords
Biological process	Differentiation
Cellular component	Secreted
Coding sequence diversity	Polymorphism
Disease	Disease mutation
Domain	Signal
Molecular function	Growth factor
PTM	Disulfide bond Glycoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological process	cell differentiation Non-traceable author statement. Source: UniProtKB insulin receptor signaling pathway Traceable author statement. Source: Reactome negative regulation of bone mineralization Inferred from direct assay Ref.16. Source: UniProtKB negative regulation of hormone secretion Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of osteoblast differentiation Inferred from direct assay Ref.16. Source: UniProtKB positive regulation of vitamin D 24-hydroxylase activity Inferred from direct assay Ref.13. Source: UniProtKB regulation of phosphate transport Inferred from direct assay Ref.8. Source: UniProtKB vitamin D catabolic process Inferred from direct assay Ref.13. Source: UniProtKB
Cellular component	extracellular space Inferred from direct assay Ref.15. Source: UniProtKB
Molecular function	growth factor activity Inferred from electronic annotation. Source: UniProtKB-KW protein tyrosine kinase activity Traceable author statement. Source: Reactome
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 24

24

Ref.7

Chain

25 – 251

227

Fibroblast growth factor 23

PRO_0000008998

Chain

25 – 179

155

Fibroblast growth factor 23 N-terminal peptide

PRO_0000352875

Chain

180 – 251

72

Fibroblast growth factor 23 C-terminal peptide

PRO_0000352876

Sites

Site

179 – 180

2

Cleavage; by proprotein convertases

Amino acid modifications

Glycosylation

178

1

O-linked (GalNAc) Ref.15

Disulfide bond

95 ↔ 113

Natural variations

Natural variant

71

1

S → G in HFTC; only the C-terminal fragment is secreted, whereas the intact protein is retained in the Golgi complex. Ref.19

VAR_023831

Natural variant

176

1

R → Q in ADHR; partially resistant to cleavage by furin. Ref.2 Ref.15

VAR_010717

Natural variant

179

1

R → Q in ADHR; C-terminal processing is abolished; reduced proteolysis by PHEX; resistant to cleavage by furin. Ref.2 Ref.8 Ref.15

VAR_010719

Natural variant

179

1

R → W in ADHR; C-terminal processing is abolished. Ref.2
Corresponds to variant rs28937882 [ dbSNP | Ensembl ].

VAR_010718

Natural variant

195

1

P → S. Ref.5
Corresponds to variant rs13312793 [ dbSNP | Ensembl ].

VAR_018887

Natural variant

239

1

T → M. Ref.2 Ref.5
Corresponds to variant rs7955866 [ dbSNP | Ensembl ].

VAR_010720

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

251

Helix Strand Turn

Details...

Beta strand

40 – 43

4

Beta strand

47 – 49

3

Beta strand

52 – 55

4

Beta strand

61 – 66

6

Turn

69 – 71

3

Beta strand

73 – 77

5

Helix

79 – 81

3

Beta strand

82 – 87

6

Turn

88 – 91

4

Beta strand

92 – 96

5

Beta strand

102 – 107

6

Turn

110 – 112

3

Beta strand

115 – 119

5

Beta strand

125 – 128

4

Turn

130 – 132

3

Beta strand

138 – 140

3

Helix

153 – 155

3

Beta strand

157 – 161

5

Helix

166 – 168

3

Sequences

	Sequence		Length	Mass (Da)
	Q9GZV9 [UniParc]. Last modified March 1, 2001. Version 1. Checksum: 6093BD0CC50C2489	FASTA	251	27,954
	10 20 30 40 50 60 MLGARLRLWV CALCSVCSMS VLRAYPNASP LLGSSWGGLI HLYTATARNS YHLQIHKNGH 70 80 90 100 110 120 VDGAPHQTIY SALMIRSEDA GFVVITGVMS RRYLCMDFRG NIFGSHYFDP ENCRFQHQTL 130 140 150 160 170 180 ENGYDVYHSP QYHFLVSLGR AKRAFLPGMN PPPYSQFLSR RNEIPLIHFN TPIPRRHTRS 190 200 210 220 230 240 AEDDSERDPL NVLKPRARMT PAPASCSQEL PSAEDNSPMA SDPLGVVRGG RVNTHAGGTG 250 PEGCRPFAKF I

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Identification of a novel fibroblast growth factor, FGF-23, preferentially expressed in the ventrolateral thalamic nucleus of the brain." Yamashita T., Yoshioka M., Itoh N. Biochem. Biophys. Res. Commun. 277:494-498(2000) [PubMed: 11032749] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23." White K.E., Evans W.E., O'Riordan J.L.H., Speer M.C., Econs M.J., Lorenz-Depiereux B., Grabowski M., Meitinger T., Strom T.M. Nat. Genet. 26:345-348(2000) [PubMed: 11062477] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, VARIANTS ADHR GLN-176; GLN-179 AND TRP-179, VARIANT MET-239.
[3]	"Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia." Shimada T., Mizutani S., Muto T., Yoneya T., Hino R., Takeda S., Takeuchi Y., Fujita T., Fukumoto S., Yamashita T. Proc. Natl. Acad. Sci. U.S.A. 98:6500-6505(2001) [PubMed: 11344269] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[4]	"The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment." Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J., Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P., Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E. , Heldens S., Huang A., Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D., Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L., Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C., Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J., Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M. Genome Res. 13:2265-2270(2003) [PubMed: 12975309] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[5]	NIEHS SNPs program Submitted (MAR-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS SER-195 AND MET-239.
[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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[7]	"Signal peptide prediction based on analysis of experimentally verified cleavage sites." Zhang Z., Henzel W.J. Protein Sci. 13:2819-2824(2004) [PubMed: 15340161] [Abstract] Cited for: PROTEIN SEQUENCE OF 25-39.
[8]	"FGF-23 inhibits renal tubular phosphate transport and is a PHEX substrate." Bowe A.E., Finnegan R., Jan de Beur S.M., Cho J., Levine M.A., Kumar R., Schiavi S.C. Biochem. Biophys. Res. Commun. 284:977-981(2001) [PubMed: 11409890] [Abstract] Cited for: FUNCTION, CHARACTERIZATION OF VARIANT ADHR GLN-179.
[9]	"The autosomal dominant hypophosphatemic rickets (ADHR) gene is a secreted polypeptide overexpressed by tumors that cause phosphate wasting." White K.E., Jonsson K.B., Carn G., Hampson G., Spector T.D., Mannstadt M., Lorenz-Depiereux B., Miyauchi A., Yang I.M., Ljunggren O., Meitinger T., Strom T.M., Jueppner H., Econs M.J. J. Clin. Endocrinol. Metab. 86:497-500(2001) [PubMed: 11157998] [Abstract] Cited for: PROTEOLYTIC PROCESSING.
[10]	"Mutant FGF-23 responsible for autosomal dominant hypophosphatemic rickets is resistant to proteolytic cleavage and causes hypophosphatemia in vivo." Shimada T., Muto T., Urakawa I., Yoneya T., Yamazaki Y., Okawa K., Takeuchi Y., Fujita T., Fukumoto S., Yamashita T. Endocrinology 143:3179-3182(2002) [PubMed: 12130585] [Abstract] Cited for: PROTEOLYTIC PROCESSING.
[11]	"FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting." Riminucci M., Collins M.T., Fedarko N.S., Cherman N., Corsi A., White K.E., Waguespack S., Gupta A., Hannon T., Econs M.J., Bianco P., Gehron Robey P. J. Clin. Invest. 112:683-692(2003) [PubMed: 12952917] [Abstract] Cited for: TISSUE SPECIFICITY.
[12]	"FGF23 is processed by proprotein convertases but not by PHEX." Benet-Pages A., Lorenz-Depiereux B., Zischka H., White K.E., Econs M.J., Strom T.M. Bone 35:455-462(2004) [PubMed: 15268897] [Abstract] Cited for: PROTEOLYTIC PROCESSING BY PROPROTEIN CONVERTASES.
[13]	"FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis." Shimada T., Hasegawa H., Yamazaki Y., Muto T., Hino R., Takeuchi Y., Fujita T., Nakahara K., Fukumoto S., Yamashita T. J. Bone Miner. Res. 19:429-435(2004) [PubMed: 15040831] [Abstract] Cited for: FUNCTION.
[14]	"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: 16597617] [Abstract] Cited for: INTERACTION WITH FGFR1; FGFR2; FGFR3 AND FGFR4, FUNCTION IN STIMULATION OF CELL PROLIFERATION.
[15]	"Polypeptide GalNAc-transferase T3 and familial tumoral calcinosis. Secretion of fibroblast growth factor 23 requires O-glycosylation." Kato K., Jeanneau C., Tarp M.A., Benet-Pages A., Lorenz-Depiereux B., Bennett E.P., Mandel U., Strom T.M., Clausen H. J. Biol. Chem. 281:18370-18377(2006) [PubMed: 16638743] [Abstract] Cited for: SUBCELLULAR LOCATION, GLYCOSYLATION AT THR-178, CHARACTERIZATION OF VARIANTS ADHR GLN-176 AND GLN-179, MASS SPECTROMETRY.
[16]	"Overexpression of fibroblast growth factor 23 suppresses osteoblast differentiation and matrix mineralization in vitro." Wang H., Yoshiko Y., Yamamoto R., Minamizaki T., Kozai K., Tanne K., Aubin J.E., Maeda N. J. Bone Miner. Res. 23:939-948(2008) [PubMed: 18282132] [Abstract] Cited for: FUNCTION.
[17]	"Fibroblast growth factor signalling: from development to cancer." Turner N., Grose R. Nat. Rev. Cancer 10:116-129(2010) [PubMed: 20094046] [Abstract] Cited for: REVIEW.
[18]	"Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members." Goetz R., Beenken A., Ibrahimi O.A., Kalinina J., Olsen S.K., Eliseenkova A.V., Xu C., Neubert T.A., Zhang F., Linhardt R.J., Yu X., White K.E., Inagaki T., Kliewer S.A., Yamamoto M., Kurosu H., Ogawa Y., Kuro-o M. , Lanske B., Razzaque M.S., Mohammadi M. Mol. Cell. Biol. 27:3417-3428(2007) [PubMed: 17339340] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.5 ANGSTROMS) OF 25-179.
[19]	"An FGF23 missense mutation causes familial tumoral calcinosis with hyperphosphatemia." Benet-Pages A., Orlik P., Strom T.M., Lorenz-Depiereux B. Hum. Mol. Genet. 14:385-390(2005) [PubMed: 15590700] [Abstract] Cited for: VARIANT HFTC GLY-71.
+	Additional computationally mapped references.

Web resources

GeneReviews

NIEHS-SNPs

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AB037973 mRNA. Translation: BAB13477.1.
AF263537 mRNA. Translation: AAG09917.1.
AB047858 mRNA. Translation: BAB55889.1.
AY358323 mRNA. Translation: AAQ88689.1.
AY566236 Genomic DNA. Translation: AAS59157.1.
BC069333 mRNA. Translation: AAH69333.1.
BC096713 mRNA. Translation: AAH96713.1.
BC098147 mRNA. Translation: AAH98147.1.
BC098252 mRNA. Translation: AAH98252.1.

IPI

IPI00026407.

RefSeq

NP_065689.1. NM_020638.2.

UniGene

Hs.287370.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2P39	X-ray	1.50	A	25-179	[»]

ProteinModelPortal

Q9GZV9.

SMR

Q9GZV9. Positions 29-170.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-58507N.

STRING

Q9GZV9.

Polymorphism databases

DMDM

13626688.

Proteomic databases

PRIDE

Q9GZV9.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000237837; ENSP00000237837; ENSG00000118972.

GeneID

8074.

KEGG

hsa:8074.

NMPDR

fig|9606.3.peg.6984.

UCSC

uc001qmq.1. human.

Organism-specific databases

CTD

8074.

GeneCards

GC12M004477.

H-InvDB

HIX0036668.

HGNC

HGNC:3680. FGF23.

MIM

193100. phenotype.
211900. phenotype.
605380. gene.

neXtProt

NX_Q9GZV9.

Orphanet

89937. Hypophosphatemic rickets.
53715. Tumoral calcinosis.

PharmGKB

PA28119.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG14965.

GeneTree

ENSGT00530000063469.

HOGENOM

HBG269053.

HOVERGEN

HBG051613.

InParanoid

Q9GZV9.

OMA

ASCSQEL.

OrthoDB

EOG4MKNH6.

PhylomeDB

Q9GZV9.

Enzyme and pathway databases

Pathway_Interaction_DB

fgf_pathway. FGF signaling pathway.

Reactome

REACT_111102. Signal Transduction.

Gene expression databases

ArrayExpress

Q9GZV9.

Bgee

Q9GZV9.

CleanEx

HS_FGF23.

Genevestigator

Q9GZV9.

GermOnline

ENSG00000118972. Homo sapiens.

Family and domain databases

InterPro

IPR008996. Cytokine_IL1-like.
IPR002348. IL1_HBGF.
[Graphical view]

KO

K04358.

PANTHER

PTHR11486. IL1_HBGF. 1 hit.

Pfam

PF00167. FGF. 1 hit.
[Graphical view]

PRINTS

PR00262. IL1HBGF.

SMART

SM00442. FGF. 1 hit.
[Graphical view]

SUPFAM

SSF50353. Cytok_IL1_like. 1 hit.

PROSITE

PS00247. HBGF_FGF. False negative.
[Graphical view]

ProtoNet

Search...

Other

NextBio

30678.

SOURCE

Search...

Entry information

Entry name

FGF23_HUMAN

Accession

Primary (citable) accession number: Q9GZV9
Secondary accession number(s): Q4V758

Entry history

Integrated into UniProtKB/Swiss-Prot:	April 27, 2001
Last sequence update:	March 1, 2001
Last modified:	January 25, 2012
This is version 121 of the entry and version 1 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.