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Q9GZV9 (FGF23_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 142. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Fibroblast growth factor 23

Short name=FGF-23
Alternative name(s):
Phosphatonin
Tumor-derived hypophosphatemia-inducing factor
Gene names
Name:FGF23
Synonyms:HYPF
ORF Names:UNQ3027/PRO9828
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length251 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence 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

Hypophosphatemic rickets, autosomal dominant (ADHR) [MIM:193100]: A disease characterized by isolated renal phosphate wasting, hypophosphatemia, and inappropriately normal 1,25-dihydroxyvitamin D3 (calcitriol) levels. Patients frequently present with bone pain, rickets, and tooth abscesses.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.2 Ref.8 Ref.15

Tumoral calcinosis, hyperphosphatemic, familial (HFTC) [MIM:211900]: A severe metabolic disorder that manifests with hyperphosphatemia and massive calcium deposits in the skin and subcutaneous tissues. Some patients manifest recurrent, transient, painful swellings of the long bones associated with the radiographic findings of periosteal reaction and cortical hyperostosis and absence of skin involvement.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.19

Sequence similarities

Belongs to the heparin-binding growth factors family.

Ontologies

Keywords
   Biological processDifferentiation
   Cellular componentSecreted
   Coding sequence diversityPolymorphism
   DiseaseDisease mutation
   DomainSignal
   Molecular functionGrowth factor
   PTMDisulfide bond
Glycoprotein
   Technical term3D-structure
Complete proteome
Direct protein sequencing
Reference proteome
Gene Ontology (GO)
   Biological_processFc-epsilon receptor signaling pathway

Traceable author statement. Source: Reactome

cell differentiation

Inferred from electronic annotation. Source: UniProtKB-KW

cellular phosphate ion homeostasis

Inferred from electronic annotation. Source: Ensembl

epidermal growth factor receptor signaling pathway

Traceable author statement. Source: Reactome

fibroblast growth factor receptor signaling pathway

Traceable author statement. Source: Reactome

innate immune response

Traceable author statement. Source: Reactome

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

neurotrophin TRK receptor signaling pathway

Traceable author statement. Source: Reactome

phosphate ion homeostasis

Inferred from mutant phenotype Ref.2. Source: UniProtKB

phosphate-containing compound metabolic process

Inferred from electronic annotation. Source: Ensembl

phosphatidylinositol-mediated signaling

Traceable author statement. Source: Reactome

positive regulation of ERK1 and ERK2 cascade

Inferred from electronic annotation. Source: Ensembl

positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway

Inferred from electronic annotation. Source: Ensembl

positive regulation of transcription, DNA-templated

Inferred from electronic annotation. Source: Ensembl

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_componentextracellular region

Traceable author statement. Source: Reactome

extracellular space

Inferred from direct assay Ref.15. Source: UniProtKB

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 2424 Ref.7
Chain25 – 251227Fibroblast growth factor 23
PRO_0000008998
Chain25 – 179155Fibroblast growth factor 23 N-terminal peptide
PRO_0000352875
Chain180 – 25172Fibroblast growth factor 23 C-terminal peptide
PRO_0000352876

Sites

Site179 – 1802Cleavage; by proprotein convertases

Amino acid modifications

Glycosylation1781O-linked (GalNAc) Ref.15
Disulfide bond95 ↔ 113

Natural variations

Natural variant711S → 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 variant1761R → Q in ADHR; partially resistant to cleavage by furin. Ref.2 Ref.15
VAR_010717
Natural variant1791R → 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 variant1791R → W in ADHR; C-terminal processing is abolished. Ref.2
Corresponds to variant rs28937882 [ dbSNP | Ensembl ].
VAR_010718
Natural variant1951P → S. Ref.5
Corresponds to variant rs13312793 [ dbSNP | Ensembl ].
VAR_018887
Natural variant2391T → M. Ref.2 Ref.5
Corresponds to variant rs7955866 [ dbSNP | Ensembl ].
VAR_010720

Secondary structure

.................................... 251
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Q9GZV9 [UniParc].

Last modified March 1, 2001. Version 1.
Checksum: 6093BD0CC50C2489

FASTA25127,954
        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 

« Hide

References

« Hide '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] [Europe PMC] [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] [Europe PMC] [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] [Europe PMC] [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. expand/collapse author list , 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] [Europe PMC] [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] [Europe PMC] [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] [Europe PMC] [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] [Europe PMC] [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] [Europe PMC] [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] [Europe PMC] [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] [Europe PMC] [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] [Europe PMC] [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] [Europe PMC] [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] [Europe PMC] [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] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION, GLYCOSYLATION AT THR-178, CHARACTERIZATION OF VARIANTS ADHR GLN-176 AND GLN-179, IDENTIFICATION BY 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] [Europe PMC] [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] [Europe PMC] [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. expand/collapse author list , Lanske B., Razzaque M.S., Mohammadi M.
Mol. Cell. Biol. 27:3417-3428(2007) [PubMed] [Europe PMC] [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] [Europe PMC] [Abstract]
Cited for: VARIANT HFTC GLY-71.
+Additional computationally mapped references.

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.
RefSeqNP_065689.1. NM_020638.2.
UniGeneHs.287370.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
2P39X-ray1.50A25-179[»]
ProteinModelPortalQ9GZV9.
SMRQ9GZV9. Positions 29-170.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid113748. 1 interaction.
DIPDIP-58507N.
STRING9606.ENSP00000237837.

PTM databases

PhosphoSiteQ9GZV9.

Polymorphism databases

DMDM13626688.

Proteomic databases

PaxDbQ9GZV9.
PRIDEQ9GZV9.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000237837; ENSP00000237837; ENSG00000118972.
GeneID8074.
KEGGhsa:8074.
UCSCuc001qmq.1. human.

Organism-specific databases

CTD8074.
GeneCardsGC12M004477.
HGNCHGNC:3680. FGF23.
MIM193100. phenotype.
211900. phenotype.
605380. gene.
neXtProtNX_Q9GZV9.
Orphanet89937. Autosomal dominant hypophosphatemic rickets.
306661. Hypercalcemic tumoral calcinosis.
PharmGKBPA28119.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG270405.
HOGENOMHOG000112573.
HOVERGENHBG051613.
InParanoidQ9GZV9.
KOK04358.
OMADVYHSPQ.
OrthoDBEOG71K63W.
PhylomeDBQ9GZV9.
TreeFamTF335872.

Enzyme and pathway databases

ReactomeREACT_111102. Signal Transduction.
REACT_116125. Disease.
REACT_6900. Immune System.

Gene expression databases

BgeeQ9GZV9.
CleanExHS_FGF23.
GenevestigatorQ9GZV9.

Family and domain databases

InterProIPR008996. Cytokine_IL1-like.
IPR028304. FGF23.
IPR002209. Fibroblast_GF_fam.
IPR028142. IL-1_fam/FGF_fam.
[Graphical view]
PANTHERPTHR11486. PTHR11486. 1 hit.
PTHR11486:SF10. PTHR11486:SF10. 1 hit.
PfamPF00167. FGF. 1 hit.
[Graphical view]
PRINTSPR00262. IL1HBGF.
SMARTSM00442. FGF. 1 hit.
[Graphical view]
SUPFAMSSF50353. SSF50353. 1 hit.
ProtoNetSearch...

Other

EvolutionaryTraceQ9GZV9.
GeneWikiFibroblast_growth_factor_23.
GenomeRNAi8074.
NextBio30678.
PROQ9GZV9.
SOURCESearch...

Entry information

Entry nameFGF23_HUMAN
AccessionPrimary (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: April 16, 2014
This is version 142 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 12

Human chromosome 12: entries, gene names and cross-references to MIM