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Protein

Forkhead box protein L2

Gene

FOXL2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-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

  • apoptotic DNA fragmentation Source: UniProtKB
  • cell differentiation Source: UniProtKB
  • embryonic eye morphogenesis Source: Ensembl
  • extraocular skeletal muscle development Source: UniProtKB
  • female somatic sex determination Source: Ensembl
  • granulosa cell differentiation Source: Ensembl
  • menstruation Source: UniProtKB
  • negative regulation of transcription, DNA-templated Source: UniProtKB
  • negative regulation of transcription from RNA polymerase II promoter Source: Ensembl
  • ovarian follicle development Source: UniProtKB
  • positive regulation of apoptotic process Source: UniProtKB
  • positive regulation of cysteine-type endopeptidase activity involved in apoptotic process Source: UniProtKB
  • positive regulation of follicle-stimulating hormone secretion Source: Ensembl
  • positive regulation of luteinizing hormone secretion Source: Ensembl
  • positive regulation of transcription, DNA-templated Source: UniProtKB
  • single fertilization Source: Ensembl
  • uterus development Source: Ensembl
Complete GO annotation...

Keywords - Biological processi

Differentiation, Transcription, Transcription regulation

Keywords - Ligandi

DNA-binding

Enzyme and pathway databases

BioCyciZFISH:G66-32534-MONOMER.
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

HGNCiHGNC:1092. FOXL2.

Subcellular locationi

  • Nucleus PROSITE-ProRule annotation1 Publication

GO - Cellular componenti

  • nucleus Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Nucleus

Pathology & Biotechi

Involvement in diseasei

Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES)12 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 rs387906920dbSNPEnsembl.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 rs28937884dbSNPEnsembl.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 Publication1
Natural variantiVAR_046495101S → R in BPES; nuclear aggregation; impaired transactivation activity. 2 Publications1
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 Publications1
Natural variantiVAR_021200105N → S in BPES; type II. 1
Natural variantiVAR_016885106L → F in BPES; sporadic; nuclear and cytoplasmic aggregation; impaired transactivation activity. 2 Publications1
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. 1
Natural variantiVAR_021203215Y → C in BPES. 2 Publications1
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 Publications1
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 rs121908359dbSNPEnsembl.1
Natural variantiVAR_021204258Y → N in POF3. 1 PublicationCorresponds to variant rs28937885dbSNPEnsembl.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.
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

PaxDbiP58012.
PeptideAtlasiP58012.
PRIDEiP58012.

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.
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

  • ubiquitin conjugating enzyme binding Source: UniProtKB

Protein-protein interaction databases

BioGridi107136. 56 interactors.
IntActiP58012. 50 interactors.
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

Sequence similaritiesi

Contains 1 fork-head DNA-binding domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiKOG2294. Eukaryota.
COG5025. LUCA.
GeneTreeiENSGT00760000118904.
HOVERGENiHBG051651.
InParanoidiP58012.
KOiK09405.
OMAiELSMMHC.
OrthoDBiEOG091G0ESH.
PhylomeDBiP58012.
TreeFamiTF316127.

Family and domain databases

Gene3Di1.10.10.10. 1 hit.
InterProiIPR001766. Fork_head_dom.
IPR033063. FoxL2.
IPR018122. TF_fork_head_CS_1.
IPR030456. TF_fork_head_CS_2.
IPR011991. WHTH_DNA-bd_dom.
[Graphical view]
PANTHERiPTHR11829:SF177. PTHR11829:SF177. 1 hit.
PfamiPF00250. Forkhead. 1 hit.
[Graphical view]
PRINTSiPR00053. FORKHEAD.
SMARTiSM00339. FH. 1 hit.
[Graphical view]
SUPFAMiSSF46785. SSF46785. 1 hit.
PROSITEiPS00657. FORK_HEAD_1. 1 hit.
PS00658. FORK_HEAD_2. 1 hit.
PS50039. FORK_HEAD_3. 1 hit.
[Graphical view]

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 rs387906920dbSNPEnsembl.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 rs28937884dbSNPEnsembl.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 Publication1
Natural variantiVAR_046495101S → R in BPES; nuclear aggregation; impaired transactivation activity. 2 Publications1
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 Publications1
Natural variantiVAR_021200105N → S in BPES; type II. 1
Natural variantiVAR_016885106L → F in BPES; sporadic; nuclear and cytoplasmic aggregation; impaired transactivation activity. 2 Publications1
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 Publications1
Natural variantiVAR_021201179A → G.2 PublicationsCorresponds to variant rs7432551dbSNPEnsembl.1
Natural variantiVAR_015181187G → D in POF3; does not affect nuclear localization; reduces transcriptional activation of OSR2. 2 PublicationsCorresponds to variant rs121908359dbSNPEnsembl.1
Natural variantiVAR_021202193K → R in BPES; type II. 1
Natural variantiVAR_021203215Y → C in BPES. 2 Publications1
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 Publications1
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 rs28937885dbSNPEnsembl.1
Natural variantiVAR_015182285P → S.1 Publication1

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

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. 56 interactors.
IntActiP58012. 50 interactors.
STRINGi9606.ENSP00000333188.

PTM databases

iPTMnetiP58012.
PhosphoSitePlusiP58012.

Polymorphism and mutation databases

BioMutaiFOXL2.
DMDMi13626838.

Proteomic databases

PaxDbiP58012.
PeptideAtlasiP58012.
PRIDEiP58012.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000330315; ENSP00000333188; ENSG00000183770.
GeneIDi668.
KEGGihsa:668.

Organism-specific databases

CTDi668.
DisGeNETi668.
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.
OMAiELSMMHC.
OrthoDBiEOG091G0ESH.
PhylomeDBiP58012.
TreeFamiTF316127.

Enzyme and pathway databases

BioCyciZFISH:G66-32534-MONOMER.
SIGNORiP58012.

Miscellaneous databases

GeneWikiiForkhead_box_L2.
GenomeRNAii668.
PROiP58012.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000183770.
CleanExiHS_FOXL2.
ExpressionAtlasiP58012. baseline and differential.
GenevisibleiP58012. HS.

Family and domain databases

Gene3Di1.10.10.10. 1 hit.
InterProiIPR001766. Fork_head_dom.
IPR033063. FoxL2.
IPR018122. TF_fork_head_CS_1.
IPR030456. TF_fork_head_CS_2.
IPR011991. WHTH_DNA-bd_dom.
[Graphical view]
PANTHERiPTHR11829:SF177. PTHR11829:SF177. 1 hit.
PfamiPF00250. Forkhead. 1 hit.
[Graphical view]
PRINTSiPR00053. FORKHEAD.
SMARTiSM00339. FH. 1 hit.
[Graphical view]
SUPFAMiSSF46785. SSF46785. 1 hit.
PROSITEiPS00657. FORK_HEAD_1. 1 hit.
PS00658. FORK_HEAD_2. 1 hit.
PS50039. FORK_HEAD_3. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiFOXL2_HUMAN
AccessioniPrimary (citable) accession number: P58012
Secondary accession number(s): Q4ZGJ3
Entry historyi
Integrated into UniProtKB/Swiss-Prot: April 27, 2001
Last sequence update: April 27, 2001
Last modified: November 30, 2016
This is version 159 of the entry and version 1 of the sequence. [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

Documents

  1. Human chromosome 3
    Human chromosome 3: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.