FOXL2_HUMAN
ID FOXL2_HUMAN Reviewed; 376 AA.
AC P58012; Q4ZGJ3;
DT 27-APR-2001, integrated into UniProtKB/Swiss-Prot.
DT 27-APR-2001, sequence version 1.
DT 03-AUG-2022, entry version 200.
DE RecName: Full=Forkhead box protein L2;
GN Name=FOXL2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT BPES
RP ALA-ALA-ALA-ALA-ALA-ALA-ALA-ALA-ALA-ALA-234 INS.
RX PubMed=11175783; DOI=10.1038/84781;
RA Crisponi L., Deiana M., Loi A., Chiappe F., Uda M., Amati P., Bisceglia L.,
RA Zelante L., Nagaraja R., Porcu S., Ristaldi M.S., Marzella R., Rocchi M.,
RA Nicolino M., Lienhardt-Roussie A., Nivelon A., Verloes A., Schlessinger D.,
RA Gasparini P., Bonneau D., Cao A., Pilia G.;
RT "The putative forkhead transcription factor FOXL2 is mutated in
RT blepharophimosis/ptosis/epicanthus inversus syndrome.";
RL Nat. Genet. 27:159-166(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT BPES
RP ALA-ALA-ALA-ALA-ALA-ALA-ALA-ALA-ALA-ALA-ALA-234 INS.
RA Xu Y.;
RT "Study of mutations of FOXL2 gene in a Chinese TongHai family with
RT blepharophimosis-ptosis-epicanthus inversus syndrome.";
RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Pancreas;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP FUNCTION IN APOPTOSIS, AND INTERACTION WITH DDX20.
RX PubMed=16153597; DOI=10.1016/j.bbrc.2005.08.184;
RA Lee K., Pisarska M.D., Ko J.J., Kang Y., Yoon S., Ryou S.M., Cha K.Y.,
RA Bae J.;
RT "Transcriptional factor FOXL2 interacts with DP103 and induces apoptosis.";
RL Biochem. Biophys. Res. Commun. 336:876-881(2005).
RN [5]
RP FUNCTION AS TRANSCRIPTIONAL REPRESSOR OF STAR, INTERACTION WITH UBE2I,
RP SUMOYLATION AT LYS-25, SUBCELLULAR LOCATION, AND MUTAGENESIS OF LYS-25.
RX PubMed=19744555; DOI=10.1016/j.cellsig.2009.09.001;
RA Kuo F.T., Bentsi-Barnes I.K., Barlow G.M., Bae J., Pisarska M.D.;
RT "Sumoylation of forkhead L2 by Ubc9 is required for its activity as a
RT transcriptional repressor of the steroidogenic acute regulatory gene.";
RL Cell. Signal. 21:1935-1944(2009).
RN [6]
RP FUNCTION AS TRANSCRIPTIONAL ACTIVATOR OF SIRT1, AND INDUCTION.
RX PubMed=19010791; DOI=10.1093/hmg/ddn389;
RA Benayoun B.A., Batista F., Auer J., Dipietromaria A., L'Hote D.,
RA De Baere E., Veitia R.A.;
RT "Positive and negative feedback regulates the transcription factor FOXL2 in
RT response to cell stress: evidence for a regulatory imbalance induced by
RT disease-causing mutations.";
RL Hum. Mol. Genet. 18:632-644(2009).
RN [7]
RP FUNCTION AS TRANSCRIPTIONAL ACTIVATOR OF OSR2, VARIANT POF3 ASP-187, AND
RP CHARACTERIZATION OF VARIANT POF3 ASP-187.
RX PubMed=19429596; DOI=10.1136/jmg.2008.065086;
RA Laissue P., Lakhal B., Benayoun B.A., Dipietromaria A., Braham R.,
RA Elghezal H., Philibert P., Saad A., Sultan C., Fellous M., Veitia R.A.;
RT "Functional evidence implicating FOXL2 in non-syndromic premature ovarian
RT failure and in the regulation of the transcription factor OSR2.";
RL J. Med. Genet. 46:455-457(2009).
RN [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-33, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [9]
RP DATABASE OF FOXL2 VARIANTS.
RX PubMed=15300845; DOI=10.1002/humu.20079;
RA Beysen D., Vandesompele J., Messiaen L., De Paepe A., De Baere E.;
RT "The human FOXL2 mutation database.";
RL Hum. Mutat. 24:189-193(2004).
RN [10]
RP VARIANTS BPES ILE-85 DEL AND PHE-217.
RX PubMed=11468277; DOI=10.1093/hmg/10.15.1591;
RA De Baere E., Dixon M.J., Small K.W., Jabs E.W., Leroy B.P., Devriendt K.,
RA Gillerot Y., Mortier G., Meire F., Van Maldergem L., Courtens W.,
RA Hjalgrim H., Huang S., Liebaers I., Van Regemorter N., Touraine P.,
RA Praphanphoj V., Verloes A., Udar N., Yellore V., Chalukya M., Yelchits S.,
RA De Paepe A., Kuttenn F., Fellous M., Veitia R., Messiaen L.;
RT "Spectrum of FOXL2 gene mutations in blepharophimosis-ptosis-epicanthus
RT inversus (BPES) families demonstrates a genotype -- phenotype
RT correlation.";
RL Hum. Mol. Genet. 10:1591-1600(2001).
RN [11]
RP VARIANT BPES ALA-ALA-ALA-ALA-ALA-ALA-ALA-ALA-ALA-ALA-234 INS.
RX PubMed=12400065; DOI=10.1002/ajmg.10741;
RA Ramirez-Castro J.L., Pineda-Trujillo N., Valencia A.V., Muneton C.M.,
RA Botero O., Trujillo O., Vasquez G., Mora B.E., Durango N., Bedoya G.,
RA Ruiz-Linares A.;
RT "Mutations in FOXL2 underlying BPES (types 1 and 2) in Colombian
RT families.";
RL Am. J. Med. Genet. 113:47-51(2002).
RN [12]
RP VARIANTS ASP-187 AND SER-285.
RX PubMed=12161610; DOI=10.1136/jmg.39.8.e43;
RA De Baere E., Lemercier B., Christin-Maitre S., Durval D., Messiaen L.,
RA Fellous M., Veitia R.;
RT "FOXL2 mutation screening in a large panel of POF patients and XX males.";
RL J. Med. Genet. 39:E43-E43(2002).
RN [13]
RP VARIANTS POF3 221-ALA--ALA-230 DEL AND ASN-258, AND VARIANT GLY-179.
RX PubMed=12149404; DOI=10.1093/molehr/8.8.729;
RA Harris S.E., Chand A.L., Winship I.M., Gersak K., Aittomaeki K.,
RA Shelling A.N.;
RT "Identification of novel mutations in FOXL2 associated with premature
RT ovarian failure.";
RL Mol. Hum. Reprod. 8:729-733(2002).
RN [14]
RP VARIANTS BPES PHE-106; LYS-109 AND PHE-217.
RX PubMed=12529855; DOI=10.1086/346118;
RA De Baere E., Beysen D., Oley C., Lorenz B., Cocquet J., De Sutter P.,
RA Devriendt K., Dixon M.J., Fellous M., Fryns J.-P., Garza A., Jonsrud C.,
RA Koivisto P.A., Krause A., Leroy B.P., Meire F., Plomp A., Van Maldergem L.,
RA De Paepe A., Veitia R., Messiaen L.;
RT "FOXL2 and BPES: mutational hotspots, phenotypic variability, and revision
RT of the genotype-phenotype correlation.";
RL Am. J. Hum. Genet. 72:478-487(2003).
RN [15]
RP VARIANT BPES SER-84.
RX PubMed=12630957; DOI=10.1034/j.1399-0004.2003.00011.x;
RA Dollfus H., Stoetzel C., Riehm S., Lahlou Boukoffa W., Bediard Boulaneb F.,
RA Quillet R., Abu-Eid M., Speeg-Schatz C., Francfort J.J., Flament J.,
RA Veillon F., Perrin-Schmitt F.;
RT "Sporadic and familial blepharophimosis -ptosis-epicanthus inversus
RT syndrome: FOXL2 mutation screen and MRI study of the superior levator
RT eyelid muscle.";
RL Clin. Genet. 63:117-120(2003).
RN [16]
RP VARIANT BPES ARG-104.
RX PubMed=12938087; DOI=10.1002/humu.10251;
RA Udar N., Yellore V., Chalukya M., Yelchits S., Silva-Garcia R., Small K.;
RT "Comparative analysis of the FOXL2 gene and characterization of mutations
RT in BPES patients.";
RL Hum. Mutat. 22:222-228(2003).
RN [17]
RP VARIANT BPES CYS-215.
RX PubMed=15257268;
RA Kumar A., Babu M., Raghunath A., Venkatesh C.P.;
RT "Genetic analysis of a five generation Indian family with BPES: a novel
RT missense mutation (p.Y215C).";
RL Mol. Vis. 10:445-449(2004).
RN [18]
RP VARIANT BPES THR-63.
RX PubMed=16454982;
RA Or S.F., Tong M.F., Lo F.M., Lam T.S.;
RT "Three novel FOXL2 gene mutations in Chinese patients with
RT blepharophimosis-ptosis-epicanthus inversus syndrome.";
RL Chin. Med. J. 119:49-52(2006).
RN [19]
RP VARIANT BPES ALA-ALA-ALA-ALA-ALA-234 INS, AND CHARACTERIZATION OF VARIANT
RP BPES ALA-ALA-ALA-ALA-ALA-234 INS.
RX PubMed=17089161; DOI=10.1007/s00439-006-0276-0;
RA Nallathambi J., Moumne L., De Baere E., Beysen D., Usha K., Sundaresan P.,
RA Veitia R.A.;
RT "A novel polyalanine expansion in FOXL2: the first evidence for a recessive
RT form of the blepharophimosis syndrome (BPES) associated with ovarian
RT dysfunction.";
RL Hum. Genet. 121:107-112(2007).
RN [20]
RP CHARACTERIZATION OF VARIANTS BPES LEU-58; VAL-66; LYS-69; THR-80; ASN-84;
RP SER-90; GLY-98; ARG-101; THR-102; CYS-103; ARG-104; PHE-106; PRO-106;
RP LYS-109 AND PHE-217.
RX PubMed=18372316; DOI=10.1093/hmg/ddn100;
RA Beysen D., Moumne L., Veitia R., Peters H., Leroy B.P., De Paepe A.,
RA De Baere E.;
RT "Missense mutations in the forkhead domain of FOXL2 lead to subcellular
RT mislocalization, protein aggregation and impaired transactivation.";
RL Hum. Mol. Genet. 17:2030-2038(2008).
RN [21]
RP VARIANTS BPES ARG-98; PRO-108; CYS-215; CYS-217 AND
RP ALA-ALA-ALA-ALA-ALA-ALA-ALA-ALA-ALA-ALA-234 INS, VARIANT GLY-179, AND
RP CHARACTERIZATION OF VARIANTS BPES PRO-108 AND CYS-217.
RX PubMed=18484667; DOI=10.1002/humu.20809;
RA Nallathambi J., Laissue P., Batista F., Benayoun B.A., Lesaffre C.,
RA Moumne L., Pandaranayaka P.E., Usha K., Krishnaswamy S., Sundaresan P.,
RA Veitia R.A.;
RT "Differential functional effects of novel mutations of the transcription
RT factor FOXL2 in BPES patients.";
RL Hum. Mutat. 29:E123-E131(2008).
RN [22]
RP VARIANTS BPES LEU-58; VAL-65; VAL-66; LYS-69; THR-80; ASN-84; SER-90;
RP GLY-98; ARG-101; THR-102; CYS-103 AND PRO-106.
RX PubMed=18642388; DOI=10.1002/humu.20819;
RA Beysen D., De Jaegere S., Amor D., Bouchard P., Christin-Maitre S.,
RA Fellous M., Touraine P., Grix A.W., Hennekam R., Meire F., Oyen N.,
RA Wilson L.C., Barel D., Clayton-Smith J., de Ravel T., Decock C.,
RA Delbeke P., Ensenauer R., Ebinger F., Gillessen-Kaesbach G., Hendriks Y.,
RA Kimonis V., Laframboise R., Laissue P., Leppig K., Leroy B.P., Miller D.T.,
RA Mowat D., Neumann L., Plomp A., Van Regemorter N., Wieczorek D.,
RA Veitia R.A., De Paepe A., De Baere E.;
RT "Identification of 34 novel and 56 known FOXL2 mutations in patients with
RT blepharophimosis syndrome.";
RL Hum. Mutat. 29:E205-E219(2008).
RN [23]
RP VARIANT TRP-134.
RX PubMed=19516027; DOI=10.1056/nejmoa0902542;
RA Shah S.P., Kobel M., Senz J., Morin R.D., Clarke B.A., Wiegand K.C.,
RA Leung G., Zayed A., Mehl E., Kalloger S.E., Sun M., Giuliany R., Yorida E.,
RA Jones S., Varhol R., Swenerton K.D., Miller D., Clement P.B., Crane C.,
RA Madore J., Provencher D., Leung P., DeFazio A., Khattra J., Turashvili G.,
RA Zhao Y., Zeng T., Glover J.N., Vanderhyden B., Zhao C., Parkinson C.A.,
RA Jimenez-Linan M., Bowtell D.D., Mes-Masson A.M., Brenton J.D.,
RA Aparicio S.A., Boyd N., Hirst M., Gilks C.B., Marra M., Huntsman D.G.;
RT "Mutation of FOXL2 in granulosa-cell tumors of the ovary.";
RL N. Engl. J. Med. 360:2719-2729(2009).
RN [24]
RP VARIANT TRP-134.
RX PubMed=19956657; DOI=10.1371/journal.pone.0007988;
RA Schrader K.A., Gorbatcheva B., Senz J., Heravi-Moussavi A., Melnyk N.,
RA Salamanca C., Maines-Bandiera S., Cooke S.L., Leung P., Brenton J.D.,
RA Gilks C.B., Monahan J., Huntsman D.G.;
RT "The specificity of the FOXL2 c.402C>G Somatic mutation: a survey of solid
RT tumors.";
RL PLoS ONE 4:E7988-E7988(2009).
RN [25]
RP VARIANT GLY-349.
RX PubMed=27610946; DOI=10.1002/humu.23116;
RA Igarashi M., Takasawa K., Hakoda A., Kanno J., Takada S., Miyado M.,
RA Baba T., Morohashi K.I., Tajima T., Hata K., Nakabayashi K., Matsubara Y.,
RA Sekido R., Ogata T., Kashimada K., Fukami M.;
RT "Identical NR5A1 missense mutations in two unrelated 46,XX individuals with
RT testicular tissues.";
RL Hum. Mutat. 38:39-42(2017).
CC -!- FUNCTION: Transcriptional regulator. Critical factor essential for
CC ovary differentiation and maintenance, and repression of the genetic
CC program for somatic testis determination. Prevents trans-
CC differentiation of ovary to testis through transcriptional repression
CC of the Sertoli cell-promoting gene SOX9 (By similarity). Has apoptotic
CC activity in ovarian cells. Suppresses ESR1-mediated transcription of
CC PTGS2/COX2 stimulated by tamoxifen (By similarity). Is a regulator of
CC CYP19 expression (By similarity). Participates in SMAD3-dependent
CC transcription of FST via the intronic SMAD-binding element (By
CC similarity). Is a transcriptional repressor of STAR. Activates SIRT1
CC transcription under cellular stress conditions. Activates transcription
CC of OSR2. {ECO:0000250, ECO:0000269|PubMed:16153597,
CC ECO:0000269|PubMed:19010791, ECO:0000269|PubMed:19429596,
CC ECO:0000269|PubMed:19744555}.
CC -!- SUBUNIT: Interacts with ESR1 (By similarity). Interacts with SMAD3 (By
CC similarity). Interacts with DDX20. Interacts with UBE2I/UBC9.
CC {ECO:0000250, ECO:0000269|PubMed:16153597,
CC ECO:0000269|PubMed:19744555}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000255|PROSITE-ProRule:PRU00089,
CC ECO:0000269|PubMed:19744555}.
CC -!- TISSUE SPECIFICITY: In addition to its expression in the developing
CC eyelid, it is transcribed very early in somatic cells of the developing
CC gonad (before sex determination) and its expression persists in the
CC follicular cells of the adult ovary.
CC -!- INDUCTION: In granulosa-like cells, up-regulated at transcript and
CC protein levels under oxidative stress and heat-shock conditions. Down-
CC regulated by SIRT1. {ECO:0000269|PubMed:19010791}.
CC -!- PTM: Sumoylated with SUMO1; sumoylation is required for transcriptional
CC repression activity. {ECO:0000269|PubMed:19744555}.
CC -!- DISEASE: Blepharophimosis, ptosis, and epicanthus inversus syndrome
CC (BPES) [MIM:110100]: A disorder characterized by eyelid dysplasia,
CC small palpebral fissures, drooping eyelids and a skin fold curving in
CC the mediolateral direction, inferior to the inner canthus. In type I
CC BPSE (BPES1) eyelid abnormalities are associated with female
CC infertility. Affected females show an ovarian deficit due to primary
CC amenorrhea or to premature ovarian failure (POF). In type II BPSE
CC (BPES2) affected individuals show only the eyelid defects.
CC {ECO:0000269|PubMed:11175783, ECO:0000269|PubMed:11468277,
CC ECO:0000269|PubMed:12400065, ECO:0000269|PubMed:12529855,
CC ECO:0000269|PubMed:12630957, ECO:0000269|PubMed:12938087,
CC ECO:0000269|PubMed:15257268, ECO:0000269|PubMed:16454982,
CC ECO:0000269|PubMed:17089161, ECO:0000269|PubMed:18372316,
CC ECO:0000269|PubMed:18484667, ECO:0000269|PubMed:18642388,
CC ECO:0000269|Ref.2}. Note=The disease is caused by variants affecting
CC the gene represented in this entry. There is a mutational hotspot in
CC the region coding for the poly-Ala domain, since 30% of all mutations
CC in the ORF lead to poly-Ala expansions, resulting mainly in BPES type
CC II.
CC -!- DISEASE: Premature ovarian failure 3 (POF3) [MIM:608996]: An ovarian
CC disorder defined as the cessation of ovarian function under the age of
CC 40 years. It is characterized by oligomenorrhea or amenorrhea, in the
CC presence of elevated levels of serum gonadotropins and low estradiol.
CC {ECO:0000269|PubMed:12149404, ECO:0000269|PubMed:19429596}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- WEB RESOURCE: Name=Forkhead box L2 (FOXL2); Note=Leiden Open Variation
CC Database (LOVD);
CC URL="https://lovd.cmgg.be/index.php?select_db=FOXL2";
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DR EMBL; AF301906; AAK01352.1; -; mRNA.
DR EMBL; DQ016609; AAY21823.1; -; Genomic_DNA.
DR EMBL; BC062549; AAH62549.1; -; mRNA.
DR CCDS; CCDS3105.1; -.
DR RefSeq; NP_075555.1; NM_023067.3.
DR AlphaFoldDB; P58012; -.
DR SMR; P58012; -.
DR BioGRID; 107136; 67.
DR IntAct; P58012; 53.
DR MINT; P58012; -.
DR STRING; 9606.ENSP00000333188; -.
DR iPTMnet; P58012; -.
DR PhosphoSitePlus; P58012; -.
DR BioMuta; FOXL2; -.
DR DMDM; 13626838; -.
DR jPOST; P58012; -.
DR MassIVE; P58012; -.
DR PaxDb; P58012; -.
DR PeptideAtlas; P58012; -.
DR PRIDE; P58012; -.
DR ProteomicsDB; 57047; -.
DR Antibodypedia; 17961; 380 antibodies from 37 providers.
DR DNASU; 668; -.
DR Ensembl; ENST00000648323.1; ENSP00000497217.1; ENSG00000183770.7.
DR GeneID; 668; -.
DR KEGG; hsa:668; -.
DR MANE-Select; ENST00000648323.1; ENSP00000497217.1; NM_023067.4; NP_075555.1.
DR CTD; 668; -.
DR DisGeNET; 668; -.
DR GeneCards; FOXL2; -.
DR GeneReviews; FOXL2; -.
DR HGNC; HGNC:1092; FOXL2.
DR HPA; ENSG00000183770; Tissue enhanced (ovary, parathyroid gland).
DR MalaCards; FOXL2; -.
DR MIM; 110100; phenotype.
DR MIM; 605597; gene.
DR MIM; 608996; phenotype.
DR neXtProt; NX_P58012; -.
DR OpenTargets; ENSG00000183770; -.
DR Orphanet; 572333; Blepharophimosis-ptosis-epicanthus inversus syndrome plus.
DR Orphanet; 572354; Blepharophimosis-ptosis-epicanthus inversus syndrome type 1.
DR Orphanet; 572361; Blepharophimosis-ptosis-epicanthus inversus syndrome type 2.
DR Orphanet; 99915; Maligant granulosa cell tumor of the ovary.
DR Orphanet; 619; NON RARE IN EUROPE: Primary ovarian failure.
DR PharmGKB; PA28235; -.
DR VEuPathDB; HostDB:ENSG00000183770; -.
DR eggNOG; KOG2294; Eukaryota.
DR GeneTree; ENSGT00940000162075; -.
DR HOGENOM; CLU_023357_1_0_1; -.
DR InParanoid; P58012; -.
DR OMA; CQMASGN; -.
DR OrthoDB; 1270467at2759; -.
DR PhylomeDB; P58012; -.
DR TreeFam; TF316127; -.
DR PathwayCommons; P58012; -.
DR Reactome; R-HSA-3232118; SUMOylation of transcription factors.
DR SignaLink; P58012; -.
DR SIGNOR; P58012; -.
DR BioGRID-ORCS; 668; 115 hits in 1102 CRISPR screens.
DR GeneWiki; Forkhead_box_L2; -.
DR GenomeRNAi; 668; -.
DR Pharos; P58012; Tbio.
DR PRO; PR:P58012; -.
DR Proteomes; UP000005640; Chromosome 3.
DR RNAct; P58012; protein.
DR Bgee; ENSG00000183770; Expressed in left ovary and 57 other tissues.
DR ExpressionAtlas; P58012; baseline and differential.
DR Genevisible; P58012; HS.
DR GO; GO:0000785; C:chromatin; ISA:NTNU_SB.
DR GO; GO:0090543; C:Flemming body; IDA:HPA.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0043028; F:cysteine-type endopeptidase regulator activity involved in apoptotic process; IMP:UniProtKB.
DR GO; GO:0003677; F:DNA binding; IDA:UniProtKB.
DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IEA:Ensembl.
DR GO; GO:0003700; F:DNA-binding transcription factor activity; ISS:UniProtKB.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISA:NTNU_SB.
DR GO; GO:0030331; F:nuclear estrogen receptor binding; IEA:Ensembl.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IBA:GO_Central.
DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; IDA:ARUK-UCL.
DR GO; GO:0031624; F:ubiquitin conjugating enzyme binding; IPI:UniProtKB.
DR GO; GO:0009653; P:anatomical structure morphogenesis; IBA:GO_Central.
DR GO; GO:0006309; P:apoptotic DNA fragmentation; IMP:UniProtKB.
DR GO; GO:0030154; P:cell differentiation; IBA:GO_Central.
DR GO; GO:0048048; P:embryonic eye morphogenesis; IEA:Ensembl.
DR GO; GO:0002074; P:extraocular skeletal muscle development; IMP:UniProtKB.
DR GO; GO:0019101; P:female somatic sex determination; IEA:Ensembl.
DR GO; GO:0060014; P:granulosa cell differentiation; IEA:Ensembl.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IEA:Ensembl.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; IDA:UniProtKB.
DR GO; GO:0001555; P:oocyte growth; IEA:Ensembl.
DR GO; GO:0001541; P:ovarian follicle development; IMP:UniProtKB.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IMP:UniProtKB.
DR GO; GO:0043280; P:positive regulation of cysteine-type endopeptidase activity involved in apoptotic process; IMP:UniProtKB.
DR GO; GO:0046881; P:positive regulation of follicle-stimulating hormone secretion; IEA:Ensembl.
DR GO; GO:0033686; P:positive regulation of luteinizing hormone secretion; IEA:Ensembl.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0007338; P:single fertilization; IEA:Ensembl.
DR GO; GO:0060065; P:uterus development; IEA:Ensembl.
DR CDD; cd00059; FH; 1.
DR Gene3D; 1.10.10.10; -; 1.
DR InterPro; IPR001766; Fork_head_dom.
DR InterPro; IPR018122; TF_fork_head_CS_1.
DR InterPro; IPR030456; TF_fork_head_CS_2.
DR InterPro; IPR036388; WH-like_DNA-bd_sf.
DR InterPro; IPR036390; WH_DNA-bd_sf.
DR Pfam; PF00250; Forkhead; 1.
DR PRINTS; PR00053; FORKHEAD.
DR SMART; SM00339; FH; 1.
DR SUPFAM; SSF46785; SSF46785; 1.
DR PROSITE; PS00657; FORK_HEAD_1; 1.
DR PROSITE; PS00658; FORK_HEAD_2; 1.
DR PROSITE; PS50039; FORK_HEAD_3; 1.
PE 1: Evidence at protein level;
KW Differentiation; Disease variant; DNA-binding; Isopeptide bond; Nucleus;
KW Phosphoprotein; Premature ovarian failure; Reference proteome;
KW Transcription; Transcription regulation; Triplet repeat expansion;
KW Ubl conjugation.
FT CHAIN 1..376
FT /note="Forkhead box protein L2"
FT /id="PRO_0000091861"
FT DNA_BIND 54..148
FT /note="Fork-head"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00089"
FT REGION 1..53
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 276..342
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 303..339
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 33
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT CROSSLNK 25
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO)"
FT VARIANT 58
FT /note="S -> L (in BPES; sporadic; nuclear and cytoplasmic
FT aggregation; impaired transactivation activity)"
FT /evidence="ECO:0000269|PubMed:18372316,
FT ECO:0000269|PubMed:18642388"
FT /id="VAR_021196"
FT VARIANT 63
FT /note="I -> T (in BPES; dbSNP:rs1315073489)"
FT /evidence="ECO:0000269|PubMed:16454982"
FT /id="VAR_062545"
FT VARIANT 65
FT /note="M -> V (in BPES; dbSNP:rs1559922621)"
FT /evidence="ECO:0000269|PubMed:18642388"
FT /id="VAR_046490"
FT VARIANT 66
FT /note="A -> V (in BPES; nuclear and cytoplasmic
FT aggregation; impaired transactivation activity)"
FT /evidence="ECO:0000269|PubMed:18372316,
FT ECO:0000269|PubMed:18642388"
FT /id="VAR_021197"
FT VARIANT 69
FT /note="E -> K (in BPES; sporadic; nuclear aggregation;
FT normal transactivation activity; dbSNP:rs387906920)"
FT /evidence="ECO:0000269|PubMed:18372316,
FT ECO:0000269|PubMed:18642388"
FT /id="VAR_021198"
FT VARIANT 80
FT /note="I -> T (in BPES; nuclear and cytoplasmic
FT aggregation; impaired transactivation activity)"
FT /evidence="ECO:0000269|PubMed:18372316,
FT ECO:0000269|PubMed:18642388"
FT /id="VAR_046491"
FT VARIANT 84
FT /note="I -> N (in BPES; nuclear and cytoplasmic
FT aggregation; impaired transactivation activity)"
FT /evidence="ECO:0000269|PubMed:18372316,
FT ECO:0000269|PubMed:18642388"
FT /id="VAR_046492"
FT VARIANT 84
FT /note="I -> S (in BPES; type I; dbSNP:rs28937884)"
FT /evidence="ECO:0000269|PubMed:12630957"
FT /id="VAR_016883"
FT VARIANT 85
FT /note="Missing (in BPES; sporadic)"
FT /evidence="ECO:0000269|PubMed:11468277"
FT /id="VAR_016884"
FT VARIANT 90
FT /note="F -> S (in BPES; nuclear and cytoplasmic
FT aggregation; impaired transactivation activity)"
FT /evidence="ECO:0000269|PubMed:18372316,
FT ECO:0000269|PubMed:18642388"
FT /id="VAR_046493"
FT VARIANT 98
FT /note="W -> G (in BPES; nuclear and cytoplasmic
FT aggregation; impaired transactivation activity)"
FT /evidence="ECO:0000269|PubMed:18372316,
FT ECO:0000269|PubMed:18642388"
FT /id="VAR_046494"
FT VARIANT 98
FT /note="W -> R (in BPES; dbSNP:rs1057516149)"
FT /evidence="ECO:0000269|PubMed:18484667"
FT /id="VAR_062546"
FT VARIANT 101
FT /note="S -> R (in BPES; nuclear aggregation; impaired
FT transactivation activity; dbSNP:rs1057516151)"
FT /evidence="ECO:0000269|PubMed:18372316,
FT ECO:0000269|PubMed:18642388"
FT /id="VAR_046495"
FT VARIANT 102
FT /note="I -> T (in BPES; nuclear and cytoplasmic
FT aggregation; impaired transactivation activity)"
FT /evidence="ECO:0000269|PubMed:18372316,
FT ECO:0000269|PubMed:18642388"
FT /id="VAR_046496"
FT VARIANT 103
FT /note="R -> C (in BPES; nuclear and cytoplasmic
FT aggregation; normal transactivation activity)"
FT /evidence="ECO:0000269|PubMed:18372316,
FT ECO:0000269|PubMed:18642388"
FT /id="VAR_046497"
FT VARIANT 104
FT /note="H -> R (in BPES; diffuse nuclear localization as
FT wild type; normal transactivation activity;
FT dbSNP:rs1057516153)"
FT /evidence="ECO:0000269|PubMed:12938087,
FT ECO:0000269|PubMed:18372316"
FT /id="VAR_021199"
FT VARIANT 105
FT /note="N -> S (in BPES; type II)"
FT /id="VAR_021200"
FT VARIANT 106
FT /note="L -> F (in BPES; sporadic; nuclear and cytoplasmic
FT aggregation; impaired transactivation activity;
FT dbSNP:rs1057516156)"
FT /evidence="ECO:0000269|PubMed:12529855,
FT ECO:0000269|PubMed:18372316"
FT /id="VAR_016885"
FT VARIANT 106
FT /note="L -> P (in BPES; nuclear and cytoplasmic
FT aggregation; impaired transactivation activity)"
FT /evidence="ECO:0000269|PubMed:18372316,
FT ECO:0000269|PubMed:18642388"
FT /id="VAR_046498"
FT VARIANT 108
FT /note="L -> P (in BPES; nuclear aggregation and cytoplasmic
FT mislocalization; impaired transactivation activity)"
FT /evidence="ECO:0000269|PubMed:18484667"
FT /id="VAR_062547"
FT VARIANT 109
FT /note="N -> K (in BPES; type II; diffuse nuclear
FT localization as wild type; impaired transactivation
FT activity)"
FT /evidence="ECO:0000269|PubMed:12529855,
FT ECO:0000269|PubMed:18372316"
FT /id="VAR_016886"
FT VARIANT 134
FT /note="C -> W (in granulosa-cell tumors of the ovary; not
FT commonly found in other tumor types; dbSNP:rs1057519865)"
FT /evidence="ECO:0000269|PubMed:19516027,
FT ECO:0000269|PubMed:19956657"
FT /id="VAR_062548"
FT VARIANT 179
FT /note="A -> G (in dbSNP:rs7432551)"
FT /evidence="ECO:0000269|PubMed:12149404,
FT ECO:0000269|PubMed:18484667"
FT /id="VAR_021201"
FT VARIANT 187
FT /note="G -> D (in POF3; does not affect nuclear
FT localization; reduces transcriptional activation of OSR2;
FT dbSNP:rs121908359)"
FT /evidence="ECO:0000269|PubMed:12161610,
FT ECO:0000269|PubMed:19429596"
FT /id="VAR_015181"
FT VARIANT 193
FT /note="K -> R (in BPES; type II; dbSNP:rs1057516162)"
FT /id="VAR_021202"
FT VARIANT 215
FT /note="Y -> C (in BPES; dbSNP:rs1057516168)"
FT /evidence="ECO:0000269|PubMed:15257268,
FT ECO:0000269|PubMed:18484667"
FT /id="VAR_021203"
FT VARIANT 217
FT /note="S -> C (in BPES; diffuse nuclear localization;
FT normal transcriptional activation)"
FT /evidence="ECO:0000269|PubMed:18484667"
FT /id="VAR_062549"
FT VARIANT 217
FT /note="S -> F (in BPES; diffuse nuclear localization;
FT increased transactivation activity; dbSNP:rs797044527)"
FT /evidence="ECO:0000269|PubMed:11468277,
FT ECO:0000269|PubMed:12529855, ECO:0000269|PubMed:18372316"
FT /id="VAR_016887"
FT VARIANT 234
FT /note="A -> AAAAAA (in BPES; significant higher cytoplasmic
FT retention compared to the wild-type protein)"
FT /evidence="ECO:0000269|PubMed:17089161"
FT /id="VAR_037303"
FT VARIANT 234
FT /note="A -> AAAAAAAAAAA (in BPES; type II)"
FT /evidence="ECO:0000269|PubMed:11175783,
FT ECO:0000269|PubMed:12400065"
FT /id="VAR_010782"
FT VARIANT 234
FT /note="A -> AAAAAAAAAAAA (in BPES)"
FT /evidence="ECO:0000269|Ref.2"
FT /id="VAR_025306"
FT VARIANT 258
FT /note="Y -> N (in POF3; dbSNP:rs28937885)"
FT /evidence="ECO:0000269|PubMed:12149404"
FT /id="VAR_021204"
FT VARIANT 285
FT /note="P -> S"
FT /evidence="ECO:0000269|PubMed:12161610"
FT /id="VAR_015182"
FT VARIANT 349
FT /note="R -> G (in dbSNP:rs201840174)"
FT /evidence="ECO:0000269|PubMed:27610946"
FT /id="VAR_078138"
FT MUTAGEN 25
FT /note="K->R: Results in reduced sumoylation. Loss of
FT transcriptional repression activity."
FT /evidence="ECO:0000269|PubMed:19744555"
SQ SEQUENCE 376 AA; 38772 MW; B4952F2A0380E533 CRC64;
MMASYPEPED AAGALLAPET GRTVKEPEGP PPSPGKGGGG GGGTAPEKPD PAQKPPYSYV
ALIAMAIRES AEKRLTLSGI YQYIIAKFPF YEKNKKGWQN SIRHNLSLNE CFIKVPREGG
GERKGNYWTL DPACEDMFEK GNYRRRRRMK RPFRPPPAHF QPGKGLFGAG GAAGGCGVAG
AGADGYGYLA PPKYLQSGFL NNSWPLPQPP SPMPYASCQM AAAAAAAAAA AAAAGPGSPG
AAAVVKGLAG PAASYGPYTR VQSMALPPGV VNSYNGLGGP PAAPPPPPHP HPHPHAHHLH
AAAAPPPAPP HHGAAAPPPG QLSPASPATA APPAPAPTSA PGLQFACARQ PELAMMHCSY
WDHDSKTGAL HSRLDL
