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Protein

Forkhead box protein L2

Gene

FOXL2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Transcriptional regulator. Critical factor essential for ovary differentiation and maintenance, and repression of the genetic program for somatic testis determination. Prevents trans-differentiation of ovary to testis through transcriptional repression of the Sertoli cell-promoting gene SOX9 (By similarity). Has apoptotic activity in ovarian cells. Suppresses ESR1-mediated transcription of PTGS2/COX2 stimulated by tamoxifen (By similarity). Is a regulator of CYP19 expression (By similarity). Participates in SMAD3-dependent transcription of FST via the intronic SMAD-binding element (By similarity). Is a transcriptional repressor of STAR. Activates SIRT1 transcription under cellular stress conditions. Activates transcription of OSR2.By similarity4 Publications

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
DNA bindingi54 – 148Fork-headPROSITE-ProRule annotationAdd BLAST95

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionDNA-binding
Biological processDifferentiation, Transcription, Transcription regulation

Enzyme and pathway databases

ReactomeiR-HSA-3232118 SUMOylation of transcription factors
SIGNORiP58012

Names & Taxonomyi

Protein namesi
Recommended name:
Forkhead box protein L2
Gene namesi
Name:FOXL2
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 3

Organism-specific databases

EuPathDBiHostDB:ENSG00000183770.5
HGNCiHGNC:1092 FOXL2
MIMi605597 gene
neXtProtiNX_P58012

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Nucleus

Pathology & Biotechi

Involvement in diseasei

Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES)13 Publications
The disease is caused by mutations affecting the gene represented in this entry. There is a mutational hotspot in the region coding for the poly-Ala domain, since 30% of all mutations in the ORF lead to poly-Ala expansions, resulting mainly in BPES type II.
Disease descriptionA disorder characterized by eyelid dysplasia, small palpebral fissures, drooping eyelids and a skin fold curving in the mediolateral direction, inferior to the inner canthus. In type I BPSE (BPES1) eyelid abnormalities are associated with female infertility. Affected females show an ovarian deficit due to primary amenorrhea or to premature ovarian failure (POF). In type II BPSE (BPES2) affected individuals show only the eyelid defects.
See also OMIM:110100
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_02119658S → L in BPES; sporadic; nuclear and cytoplasmic aggregation; impaired transactivation activity. 2 Publications1
Natural variantiVAR_06254563I → T in BPES. 1 Publication1
Natural variantiVAR_04649065M → V in BPES. 1 Publication1
Natural variantiVAR_02119766A → V in BPES; nuclear and cytoplasmic aggregation; impaired transactivation activity. 2 Publications1
Natural variantiVAR_02119869E → K in BPES; sporadic; nuclear aggregation; normal transactivation activity. 2 PublicationsCorresponds to variant dbSNP:rs387906920EnsemblClinVar.1
Natural variantiVAR_04649180I → T in BPES; nuclear and cytoplasmic aggregation; impaired transactivation activity. 2 Publications1
Natural variantiVAR_04649284I → N in BPES; nuclear and cytoplasmic aggregation; impaired transactivation activity. 2 Publications1
Natural variantiVAR_01688384I → S in BPES; type I. 1 PublicationCorresponds to variant dbSNP:rs28937884EnsemblClinVar.1
Natural variantiVAR_01688485Missing in BPES; sporadic. 1 Publication1
Natural variantiVAR_04649390F → S in BPES; nuclear and cytoplasmic aggregation; impaired transactivation activity. 2 Publications1
Natural variantiVAR_04649498W → G in BPES; nuclear and cytoplasmic aggregation; impaired transactivation activity. 2 Publications1
Natural variantiVAR_06254698W → R in BPES. 1 PublicationCorresponds to variant dbSNP:rs1057516149Ensembl.1
Natural variantiVAR_046495101S → R in BPES; nuclear aggregation; impaired transactivation activity. 2 PublicationsCorresponds to variant dbSNP:rs1057516151Ensembl.1
Natural variantiVAR_046496102I → T in BPES; nuclear and cytoplasmic aggregation; impaired transactivation activity. 2 Publications1
Natural variantiVAR_046497103R → C in BPES; nuclear and cytoplasmic aggregation; normal transactivation activity. 2 Publications1
Natural variantiVAR_021199104H → R in BPES; diffuse nuclear localization as wild type; normal transactivation activity. 2 PublicationsCorresponds to variant dbSNP:rs1057516153Ensembl.1
Natural variantiVAR_021200105N → S in BPES; type II. 1
Natural variantiVAR_016885106L → F in BPES; sporadic; nuclear and cytoplasmic aggregation; impaired transactivation activity. 2 PublicationsCorresponds to variant dbSNP:rs1057516156Ensembl.1
Natural variantiVAR_046498106L → P in BPES; nuclear and cytoplasmic aggregation; impaired transactivation activity. 2 Publications1
Natural variantiVAR_062547108L → P in BPES; nuclear aggregation and cytoplasmic mislocalization; impaired transactivation activity. 1 Publication1
Natural variantiVAR_016886109N → K in BPES; type II; diffuse nuclear localization as wild type; impaired transactivation activity. 2 Publications1
Natural variantiVAR_021202193K → R in BPES; type II. Corresponds to variant dbSNP:rs1057516162Ensembl.1
Natural variantiVAR_021203215Y → C in BPES. 2 PublicationsCorresponds to variant dbSNP:rs1057516168Ensembl.1
Natural variantiVAR_062549217S → C in BPES; diffuse nuclear localization; normal transcriptional activation. 1 Publication1
Natural variantiVAR_016887217S → F in BPES; diffuse nuclear localization; increased transactivation activity. 3 PublicationsCorresponds to variant dbSNP:rs797044527EnsemblClinVar.1
Natural variantiVAR_037303234A → AAAAAA in BPES; significant higher cytoplasmic retention compared to the wild-type protein. 1 Publication1
Natural variantiVAR_010782234A → AAAAAAAAAAA in BPES; type II. 2 Publications1
Natural variantiVAR_025306234A → AAAAAAAAAAAA in BPES. 1 Publication1
Premature ovarian failure 3 (POF3)2 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionAn ovarian disorder defined as the cessation of ovarian function under the age of 40 years. It is characterized by oligomenorrhea or amenorrhea, in the presence of elevated levels of serum gonadotropins and low estradiol.
See also OMIM:608996
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_015181187G → D in POF3; does not affect nuclear localization; reduces transcriptional activation of OSR2. 2 PublicationsCorresponds to variant dbSNP:rs121908359EnsemblClinVar.1
Natural variantiVAR_021204258Y → N in POF3. 1 PublicationCorresponds to variant dbSNP:rs28937885EnsemblClinVar.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi25K → R: Results in reduced sumoylation. Loss of transcriptional repression activity. 1 Publication1

Keywords - Diseasei

Disease mutation, Premature ovarian failure

Organism-specific databases

DisGeNETi668
GeneReviewsiFOXL2
MalaCardsiFOXL2
MIMi110100 phenotype
608996 phenotype
OpenTargetsiENSG00000183770
Orphaneti261559 Blepharophimosis - epicanthus inversus - ptosis due to 3q23 microdeletion
261572 Blepharophimosis - epicanthus inversus - ptosis due to a point mutation
619 Primary ovarian failure
PharmGKBiPA28235

Polymorphism and mutation databases

BioMutaiFOXL2
DMDMi13626838

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000918611 – 376Forkhead box protein L2Add BLAST376

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Cross-linki25Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO)
Modified residuei33PhosphoserineCombined sources1

Post-translational modificationi

Sumoylated with SUMO1; sumoylation is required for transcriptional repression activity.1 Publication

Keywords - PTMi

Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiP58012
PaxDbiP58012
PeptideAtlasiP58012
PRIDEiP58012
ProteomicsDBi57047

PTM databases

iPTMnetiP58012
PhosphoSitePlusiP58012

Expressioni

Tissue specificityi

In addition to its expression in the developing eyelid, it is transcribed very early in somatic cells of the developing gonad (before sex determination) and its expression persists in the follicular cells of the adult ovary.

Inductioni

In granulosa-like cells, up-regulated at transcript and protein levels under oxidative stress and heat-shock conditions. Down-regulated by SIRT1.1 Publication

Gene expression databases

BgeeiENSG00000183770 Expressed in 49 organ(s), highest expression level in female gonad
CleanExiHS_FOXL2
ExpressionAtlasiP58012 baseline and differential
GenevisibleiP58012 HS

Organism-specific databases

HPAiHPA069613

Interactioni

Subunit structurei

Interacts with ESR1 (By similarity). Interacts with SMAD3 (By similarity). Interacts with DDX20. Interacts with UBE2I/UBC9.By similarity2 Publications

GO - Molecular functioni

Protein-protein interaction databases

BioGridi107136, 66 interactors
IntActiP58012, 50 interactors
MINTiP58012
STRINGi9606.ENSP00000333188

Structurei

3D structure databases

ProteinModelPortaliP58012
SMRiP58012
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi35 – 43Poly-Gly9
Compositional biasi221 – 234Poly-AlaAdd BLAST14
Compositional biasi284 – 292Poly-Pro9
Compositional biasi301 – 304Poly-Ala4

Phylogenomic databases

eggNOGiKOG2294 Eukaryota
COG5025 LUCA
GeneTreeiENSGT00760000118904
HOVERGENiHBG051651
InParanoidiP58012
KOiK09405
OMAiSMMHCSY
OrthoDBiEOG091G0ESH
PhylomeDBiP58012
TreeFamiTF316127

Family and domain databases

CDDicd00059 FH, 1 hit
Gene3Di1.10.10.10, 1 hit
InterProiView protein in InterPro
IPR001766 Fork_head_dom
IPR018122 TF_fork_head_CS_1
IPR030456 TF_fork_head_CS_2
IPR036388 WH-like_DNA-bd_sf
IPR036390 WH_DNA-bd_sf
PfamiView protein in Pfam
PF00250 Forkhead, 1 hit
PRINTSiPR00053 FORKHEAD
SMARTiView protein in SMART
SM00339 FH, 1 hit
SUPFAMiSSF46785 SSF46785, 1 hit
PROSITEiView protein in PROSITE
PS00657 FORK_HEAD_1, 1 hit
PS00658 FORK_HEAD_2, 1 hit
PS50039 FORK_HEAD_3, 1 hit

Sequencei

Sequence statusi: Complete.

P58012-1 [UniParc]FASTAAdd to basket
« Hide
        10         20         30         40         50
MMASYPEPED AAGALLAPET GRTVKEPEGP PPSPGKGGGG GGGTAPEKPD
60 70 80 90 100
PAQKPPYSYV ALIAMAIRES AEKRLTLSGI YQYIIAKFPF YEKNKKGWQN
110 120 130 140 150
SIRHNLSLNE CFIKVPREGG GERKGNYWTL DPACEDMFEK GNYRRRRRMK
160 170 180 190 200
RPFRPPPAHF QPGKGLFGAG GAAGGCGVAG AGADGYGYLA PPKYLQSGFL
210 220 230 240 250
NNSWPLPQPP SPMPYASCQM AAAAAAAAAA AAAAGPGSPG AAAVVKGLAG
260 270 280 290 300
PAASYGPYTR VQSMALPPGV VNSYNGLGGP PAAPPPPPHP HPHPHAHHLH
310 320 330 340 350
AAAAPPPAPP HHGAAAPPPG QLSPASPATA APPAPAPTSA PGLQFACARQ
360 370
PELAMMHCSY WDHDSKTGAL HSRLDL
Length:376
Mass (Da):38,772
Last modified:April 27, 2001 - v1
Checksum:iB4952F2A0380E533
GO

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_02119658S → L in BPES; sporadic; nuclear and cytoplasmic aggregation; impaired transactivation activity. 2 Publications1
Natural variantiVAR_06254563I → T in BPES. 1 Publication1
Natural variantiVAR_04649065M → V in BPES. 1 Publication1
Natural variantiVAR_02119766A → V in BPES; nuclear and cytoplasmic aggregation; impaired transactivation activity. 2 Publications1
Natural variantiVAR_02119869E → K in BPES; sporadic; nuclear aggregation; normal transactivation activity. 2 PublicationsCorresponds to variant dbSNP:rs387906920EnsemblClinVar.1
Natural variantiVAR_04649180I → T in BPES; nuclear and cytoplasmic aggregation; impaired transactivation activity. 2 Publications1
Natural variantiVAR_04649284I → N in BPES; nuclear and cytoplasmic aggregation; impaired transactivation activity. 2 Publications1
Natural variantiVAR_01688384I → S in BPES; type I. 1 PublicationCorresponds to variant dbSNP:rs28937884EnsemblClinVar.1
Natural variantiVAR_01688485Missing in BPES; sporadic. 1 Publication1
Natural variantiVAR_04649390F → S in BPES; nuclear and cytoplasmic aggregation; impaired transactivation activity. 2 Publications1
Natural variantiVAR_04649498W → G in BPES; nuclear and cytoplasmic aggregation; impaired transactivation activity. 2 Publications1
Natural variantiVAR_06254698W → R in BPES. 1 PublicationCorresponds to variant dbSNP:rs1057516149Ensembl.1
Natural variantiVAR_046495101S → R in BPES; nuclear aggregation; impaired transactivation activity. 2 PublicationsCorresponds to variant dbSNP:rs1057516151Ensembl.1
Natural variantiVAR_046496102I → T in BPES; nuclear and cytoplasmic aggregation; impaired transactivation activity. 2 Publications1
Natural variantiVAR_046497103R → C in BPES; nuclear and cytoplasmic aggregation; normal transactivation activity. 2 Publications1
Natural variantiVAR_021199104H → R in BPES; diffuse nuclear localization as wild type; normal transactivation activity. 2 PublicationsCorresponds to variant dbSNP:rs1057516153Ensembl.1
Natural variantiVAR_021200105N → S in BPES; type II. 1
Natural variantiVAR_016885106L → F in BPES; sporadic; nuclear and cytoplasmic aggregation; impaired transactivation activity. 2 PublicationsCorresponds to variant dbSNP:rs1057516156Ensembl.1
Natural variantiVAR_046498106L → P in BPES; nuclear and cytoplasmic aggregation; impaired transactivation activity. 2 Publications1
Natural variantiVAR_062547108L → P in BPES; nuclear aggregation and cytoplasmic mislocalization; impaired transactivation activity. 1 Publication1
Natural variantiVAR_016886109N → K in BPES; type II; diffuse nuclear localization as wild type; impaired transactivation activity. 2 Publications1
Natural variantiVAR_062548134C → W in granulosa-cell tumors of the ovary; not commonly found in other tumor types. 2 PublicationsCorresponds to variant dbSNP:rs1057519865Ensembl.1
Natural variantiVAR_021201179A → G2 PublicationsCorresponds to variant dbSNP:rs7432551EnsemblClinVar.1
Natural variantiVAR_015181187G → D in POF3; does not affect nuclear localization; reduces transcriptional activation of OSR2. 2 PublicationsCorresponds to variant dbSNP:rs121908359EnsemblClinVar.1
Natural variantiVAR_021202193K → R in BPES; type II. Corresponds to variant dbSNP:rs1057516162Ensembl.1
Natural variantiVAR_021203215Y → C in BPES. 2 PublicationsCorresponds to variant dbSNP:rs1057516168Ensembl.1
Natural variantiVAR_062549217S → C in BPES; diffuse nuclear localization; normal transcriptional activation. 1 Publication1
Natural variantiVAR_016887217S → F in BPES; diffuse nuclear localization; increased transactivation activity. 3 PublicationsCorresponds to variant dbSNP:rs797044527EnsemblClinVar.1
Natural variantiVAR_037303234A → AAAAAA in BPES; significant higher cytoplasmic retention compared to the wild-type protein. 1 Publication1
Natural variantiVAR_010782234A → AAAAAAAAAAA in BPES; type II. 2 Publications1
Natural variantiVAR_025306234A → AAAAAAAAAAAA in BPES. 1 Publication1
Natural variantiVAR_021204258Y → N in POF3. 1 PublicationCorresponds to variant dbSNP:rs28937885EnsemblClinVar.1
Natural variantiVAR_015182285P → S1 Publication1
Natural variantiVAR_078138349R → G1 PublicationCorresponds to variant dbSNP:rs201840174EnsemblClinVar.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF301906 mRNA Translation: AAK01352.1
DQ016609 Genomic DNA Translation: AAY21823.1
BC062549 mRNA Translation: AAH62549.1
CCDSiCCDS3105.1
RefSeqiNP_075555.1, NM_023067.3
UniGeneiHs.289292

Genome annotation databases

EnsembliENST00000330315; ENSP00000333188; ENSG00000183770
GeneIDi668
KEGGihsa:668

Keywords - Coding sequence diversityi

Polymorphism, Triplet repeat expansion

Similar proteinsi

Cross-referencesi

Web resourcesi

Forkhead box L2 (FOXL2)

Leiden Open Variation Database (LOVD)

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF301906 mRNA Translation: AAK01352.1
DQ016609 Genomic DNA Translation: AAY21823.1
BC062549 mRNA Translation: AAH62549.1
CCDSiCCDS3105.1
RefSeqiNP_075555.1, NM_023067.3
UniGeneiHs.289292

3D structure databases

ProteinModelPortaliP58012
SMRiP58012
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi107136, 66 interactors
IntActiP58012, 50 interactors
MINTiP58012
STRINGi9606.ENSP00000333188

PTM databases

iPTMnetiP58012
PhosphoSitePlusiP58012

Polymorphism and mutation databases

BioMutaiFOXL2
DMDMi13626838

Proteomic databases

EPDiP58012
PaxDbiP58012
PeptideAtlasiP58012
PRIDEiP58012
ProteomicsDBi57047

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000330315; ENSP00000333188; ENSG00000183770
GeneIDi668
KEGGihsa:668

Organism-specific databases

CTDi668
DisGeNETi668
EuPathDBiHostDB:ENSG00000183770.5
GeneCardsiFOXL2
GeneReviewsiFOXL2
HGNCiHGNC:1092 FOXL2
HPAiHPA069613
MalaCardsiFOXL2
MIMi110100 phenotype
605597 gene
608996 phenotype
neXtProtiNX_P58012
OpenTargetsiENSG00000183770
Orphaneti261559 Blepharophimosis - epicanthus inversus - ptosis due to 3q23 microdeletion
261572 Blepharophimosis - epicanthus inversus - ptosis due to a point mutation
619 Primary ovarian failure
PharmGKBiPA28235
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG2294 Eukaryota
COG5025 LUCA
GeneTreeiENSGT00760000118904
HOVERGENiHBG051651
InParanoidiP58012
KOiK09405
OMAiSMMHCSY
OrthoDBiEOG091G0ESH
PhylomeDBiP58012
TreeFamiTF316127

Enzyme and pathway databases

ReactomeiR-HSA-3232118 SUMOylation of transcription factors
SIGNORiP58012

Miscellaneous databases

GeneWikiiForkhead_box_L2
GenomeRNAii668
PROiPR:P58012
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000183770 Expressed in 49 organ(s), highest expression level in female gonad
CleanExiHS_FOXL2
ExpressionAtlasiP58012 baseline and differential
GenevisibleiP58012 HS

Family and domain databases

CDDicd00059 FH, 1 hit
Gene3Di1.10.10.10, 1 hit
InterProiView protein in InterPro
IPR001766 Fork_head_dom
IPR018122 TF_fork_head_CS_1
IPR030456 TF_fork_head_CS_2
IPR036388 WH-like_DNA-bd_sf
IPR036390 WH_DNA-bd_sf
PfamiView protein in Pfam
PF00250 Forkhead, 1 hit
PRINTSiPR00053 FORKHEAD
SMARTiView protein in SMART
SM00339 FH, 1 hit
SUPFAMiSSF46785 SSF46785, 1 hit
PROSITEiView protein in PROSITE
PS00657 FORK_HEAD_1, 1 hit
PS00658 FORK_HEAD_2, 1 hit
PS50039 FORK_HEAD_3, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiFOXL2_HUMAN
AccessioniPrimary (citable) accession number: P58012
Secondary accession number(s): Q4ZGJ3
Entry historyiIntegrated into UniProtKB/Swiss-Prot: April 27, 2001
Last sequence update: April 27, 2001
Last modified: September 12, 2018
This is version 175 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (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.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health

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