ID   PHA4_CAEEL              Reviewed;         506 AA.
AC   Q17381; Q1HAZ5; Q1HAZ6;
DT   10-JUL-2007, integrated into UniProtKB/Swiss-Prot.
DT   01-NOV-1996, sequence version 1.
DT   27-MAR-2024, entry version 182.
DE   RecName: Full=Defective pharyngeal development protein 4;
DE   AltName: Full=Ce-fkh-1;
DE   AltName: Full=Fork head-HNF-3 homolog;
GN   Name=pha-4 {ECO:0000312|WormBase:F38A6.1a};
GN   Synonyms=fkh-1 {ECO:0000312|WormBase:F38A6.1a}; ORFNames=F38A6.1;
OS   Caenorhabditis elegans.
OC   Eukaryota; Metazoa; Ecdysozoa; Nematoda; Chromadorea; Rhabditida;
OC   Rhabditina; Rhabditomorpha; Rhabditoidea; Rhabditidae; Peloderinae;
OC   Caenorhabditis.
OX   NCBI_TaxID=6239;
RN   [1] {ECO:0000305, ECO:0000312|EMBL:AAA96319.1}
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS A; B AND C), TISSUE SPECIFICITY,
RP   DEVELOPMENTAL STAGE, AND ALTERNATIVE SPLICING.
RC   STRAIN=Bristol N2 {ECO:0000312|EMBL:AAA96319.1};
RX   PubMed=8812130; DOI=10.1006/dbio.1996.0219;
RA   Azzaria M., Goszczynski B., Chung M.A., Kalb J.M., McGhee J.D.;
RT   "A fork head/HNF-3 homolog expressed in the pharynx and intestine of the
RT   Caenorhabditis elegans embryo.";
RL   Dev. Biol. 178:289-303(1996).
RN   [2] {ECO:0000312|EMBL:CAB07378.1}
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=Bristol N2;
RX   PubMed=9851916; DOI=10.1126/science.282.5396.2012;
RG   The C. elegans sequencing consortium;
RT   "Genome sequence of the nematode C. elegans: a platform for investigating
RT   biology.";
RL   Science 282:2012-2018(1998).
RN   [3] {ECO:0000305}
RP   FUNCTION, AND DISRUPTION PHENOTYPE.
RX   PubMed=7607089; DOI=10.1242/dev.120.10.3019;
RA   Mango S.E., Lambie E.J., Kimble J.;
RT   "The pha-4 gene is required to generate the pharyngeal primordium of
RT   Caenorhabditis elegans.";
RL   Development 120:3019-3031(1994).
RN   [4] {ECO:0000305}
RP   FUNCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX   PubMed=9584117; DOI=10.1242/dev.125.12.2171;
RA   Kalb J.M., Lau K.K., Goszczynski B., Fukushige T., Moons D., Okkema P.G.,
RA   McGhee J.D.;
RT   "pha-4 is Ce-fkh-1, a fork head/HNF-3alpha,beta,gamma homolog that
RT   functions in organogenesis of the C. elegans pharynx.";
RL   Development 125:2171-2180(1998).
RN   [5] {ECO:0000305}
RP   FUNCTION, SUBCELLULAR LOCATION, AND DEVELOPMENTAL STAGE.
RX   PubMed=9649499; DOI=10.1101/gad.12.13.1947;
RA   Horner M.A., Quintin S., Domeier M.E., Kimble J., Labouesse M., Mango S.E.;
RT   "pha-4, an HNF-3 homolog, specifies pharyngeal organ identity in
RT   Caenorhabditis elegans.";
RL   Genes Dev. 12:1947-1952(1998).
RN   [6] {ECO:0000305}
RP   FUNCTION.
RX   PubMed=11823633; DOI=10.1126/science.1065175;
RA   Gaudet J., Mango S.E.;
RT   "Regulation of organogenesis by the Caenorhabditis elegans FoxA protein
RT   PHA-4.";
RL   Science 295:821-825(2002).
RN   [7] {ECO:0000305}
RP   FUNCTION.
RX   PubMed=14738885; DOI=10.1016/j.ydbio.2003.10.015;
RA   Vilimas T., Abraham A., Okkema P.G.;
RT   "An early pharyngeal muscle enhancer from the Caenorhabditis elegans ceh-22
RT   gene is targeted by the forkhead factor PHA-4.";
RL   Dev. Biol. 266:388-398(2004).
RN   [8] {ECO:0000305}
RP   DEVELOPMENTAL STAGE.
RX   PubMed=15737928; DOI=10.1016/j.devcel.2004.12.019;
RA   Grosshans H., Johnson T., Reinert K.L., Gerstein M., Slack F.J.;
RT   "The temporal patterning microRNA let-7 regulates several transcription
RT   factors at the larval to adult transition in C. elegans.";
RL   Dev. Cell 8:321-330(2005).
RN   [9] {ECO:0000305}
RP   FUNCTION, AND MUTAGENESIS OF LEU-158.
RX   PubMed=16127716; DOI=10.1002/dvdy.20550;
RA   Kaltenbach L.S., Updike D.L., Mango S.E.;
RT   "Contribution of the amino and carboxyl termini for PHA-4/FoxA function in
RT   Caenorhabditis elegans.";
RL   Dev. Dyn. 234:346-354(2005).
RN   [10] {ECO:0000305}
RP   FUNCTION.
RX   PubMed=17009877; DOI=10.1371/journal.pgen.0020161;
RA   Updike D.L., Mango S.E.;
RT   "Temporal regulation of foregut development by HTZ-1/H2A.Z and PHA-
RT   4/FoxA.";
RL   PLoS Genet. 2:1500-1510(2006).
RN   [11] {ECO:0000305}
RP   FUNCTION.
RX   PubMed=17005176; DOI=10.1016/j.ydbio.2006.08.023;
RA   Smith P.A., Mango S.E.;
RT   "Role of T-box gene tbx-2 for anterior foregut muscle development in C.
RT   elegans.";
RL   Dev. Biol. 302:25-39(2007).
RN   [12]
RP   FUNCTION.
RX   PubMed=17049341; DOI=10.1016/j.ydbio.2006.09.036;
RA   Raharjo I., Gaudet J.;
RT   "Gland-specific expression of C. elegans hlh-6 requires the combinatorial
RT   action of three distinct promoter elements.";
RL   Dev. Biol. 302:295-308(2007).
RN   [13]
RP   TISSUE SPECIFICITY.
RX   PubMed=17113066; DOI=10.1016/j.ydbio.2006.10.024;
RA   McGhee J.D., Sleumer M.C., Bilenky M., Wong K., McKay S.J., Goszczynski B.,
RA   Tian H., Krich N.D., Khattra J., Holt R.A., Baillie D.L., Kohara Y.,
RA   Marra M.A., Jones S.J., Moerman D.G., Robertson A.G.;
RT   "The ELT-2 GATA-factor and the global regulation of transcription in the C.
RT   elegans intestine.";
RL   Dev. Biol. 302:627-645(2007).
RN   [14]
RP   FUNCTION, AND DEVELOPMENTAL STAGE.
RX   PubMed=17250823; DOI=10.1016/j.ydbio.2006.11.042;
RA   Kiefer J.C., Smith P.A., Mango S.E.;
RT   "PHA-4/FoxA cooperates with TAM-1/TRIM to regulate cell fate restriction in
RT   the C. elegans foregut.";
RL   Dev. Biol. 303:611-624(2007).
RN   [15]
RP   FUNCTION, AND SUBCELLULAR LOCATION.
RX   PubMed=17476212; DOI=10.1038/nature05837;
RA   Panowski S.H., Wolff S., Aguilaniu H., Durieux J., Dillin A.;
RT   "PHA-4/Foxa mediates diet-restriction-induced longevity of C. elegans.";
RL   Nature 447:550-555(2007).
RN   [16]
RP   FUNCTION, AND INTERACTION WITH ELT-2.
RX   PubMed=18448117; DOI=10.1016/j.jmb.2007.11.103;
RA   Anokye-Danso F., Anyanful A., Sakube Y., Kagawa H.;
RT   "Transcription factors GATA/ELT-2 and forkhead/HNF-3/PHA-4 regulate the
RT   tropomyosin gene expression in the pharynx and intestine of Caenorhabditis
RT   elegans.";
RL   J. Mol. Biol. 379:201-211(2008).
RN   [17]
RP   FUNCTION.
RX   PubMed=20714352; DOI=10.1371/journal.pgen.1001060;
RA   Fakhouri T.H., Stevenson J., Chisholm A.D., Mango S.E.;
RT   "Dynamic chromatin organization during foregut development mediated by the
RT   organ selector gene PHA-4/FoxA.";
RL   PLoS Genet. 6:0-0(2010).
RN   [18]
RP   DISRUPTION PHENOTYPE.
RX   PubMed=30965033; DOI=10.1016/j.devcel.2019.03.010;
RA   Kumar S., Egan B.M., Kocsisova Z., Schneider D.L., Murphy J.T., Diwan A.,
RA   Kornfeld K.;
RT   "Lifespan extension in C. elegans caused by bacterial colonization of the
RT   intestine and subsequent activation of an innate immune response.";
RL   Dev. Cell 49:100-117(2019).
CC   -!- FUNCTION: Acts as a transcription factor required for formation of the
CC       pharyngeal primordium (PubMed:7607089, PubMed:18448117). Binds to the
CC       consensus sequence 5'-T[AG]TT[TG][AG][TC]-3' with variations of the
CC       sequence affecting onset of target gene expression (PubMed:18448117).
CC       Becomes associated with pharyngeal target promoters by the 8E cell
CC       stage, playing a role in inducing large-scale chromatin decompaction,
CC       prior to the activation of transcription (PubMed:20714352). Binding
CC       with target sequences in pharyngeal cells may be repressed by the
CC       nuclear lamina protein emr-1 (PubMed:20714352). Activates a wide array
CC       of pharyngeal genes including ceh-22, pax-1 and myo-2 and represses
CC       ectodermal genes lin-26 and elt-3, ensuring pharyngeal cell fate
CC       (PubMed:11823633, PubMed:20714352, PubMed:9584117, PubMed:14738885).
CC       Required for recruitment of htz-1 to a subset of pharyngeal promoters
CC       to ensure gene activation and also acts synergistically with tbx-2 in
CC       pharyngeal development. Acts in the regulation of diet-restriction-
CC       mediated longevity by increasing expression of sod-1, sod-2, sod-4 and
CC       sod-5 but not sod-3 (PubMed:17476212). Positively regulates the
CC       expression of the transcription factor hlh-6 in the pharyngeal gland
CC       (PubMed:17049341). May regulate gene expression in the intestine
CC       (PubMed:18448117). {ECO:0000269|PubMed:11823633,
CC       ECO:0000269|PubMed:14738885, ECO:0000269|PubMed:16127716,
CC       ECO:0000269|PubMed:17005176, ECO:0000269|PubMed:17009877,
CC       ECO:0000269|PubMed:17049341, ECO:0000269|PubMed:17250823,
CC       ECO:0000269|PubMed:17476212, ECO:0000269|PubMed:18448117,
CC       ECO:0000269|PubMed:20714352, ECO:0000269|PubMed:7607089,
CC       ECO:0000269|PubMed:9584117, ECO:0000269|PubMed:9649499}.
CC   -!- SUBUNIT: Interacts with elt-2. {ECO:0000269|PubMed:18448117}.
CC   -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000255|PROSITE-ProRule:PRU00089,
CC       ECO:0000269|PubMed:17476212, ECO:0000269|PubMed:9584117,
CC       ECO:0000269|PubMed:9649499}. Note=Present in nuclei of all cells of
CC       larval and adult pharynx but variable in neuronal nuclei.
CC       {ECO:0000269|PubMed:17476212, ECO:0000269|PubMed:9584117,
CC       ECO:0000269|PubMed:9649499}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=3;
CC       Name=a {ECO:0000312|WormBase:F38A6.1a}; Synonyms=I
CC       {ECO:0000303|PubMed:8812130};
CC         IsoId=Q17381-1; Sequence=Displayed;
CC       Name=b {ECO:0000312|WormBase:F38A6.1b}; Synonyms=II
CC       {ECO:0000303|PubMed:8812130};
CC         IsoId=Q17381-2; Sequence=VSP_052482;
CC       Name=c {ECO:0000312|WormBase:F38A6.1c}; Synonyms=III
CC       {ECO:0000303|PubMed:8812130};
CC         IsoId=Q17381-3; Sequence=VSP_052483;
CC   -!- TISSUE SPECIFICITY: Strongly expressed in the embryonic pharynx,
CC       particularly pharyngeal primordium precursor cells. Expression less
CC       strong in the embryonic gut. Expressed in adult intestine
CC       (PubMed:17113066). {ECO:0000269|PubMed:17113066,
CC       ECO:0000269|PubMed:8812130, ECO:0000269|PubMed:9584117}.
CC   -!- DEVELOPMENTAL STAGE: Expression first seen at the 8E cell stage in the
CC       embryonic gut. After hatching, expression is almost diminished in the
CC       pharynx and gut. Expressed in L3/L4 larvae in cells of the developing
CC       gonad. At the 8-12E stage, expression is seen for the first time in the
CC       rectal precursors. Intestinal expression is down-regulated during the
CC       larval to adult transition. {ECO:0000269|PubMed:15737928,
CC       ECO:0000269|PubMed:17250823, ECO:0000269|PubMed:8812130,
CC       ECO:0000269|PubMed:9649499}.
CC   -!- DISRUPTION PHENOTYPE: Worms are unable to form the pharyngeal
CC       primordium with the pharyngeal precursor cells, ABaraapapaa and
CC       ABaraapppaa showing arrested development prior to terminal cell
CC       division. Some mutants exhibit malformed rectal tissues and fail to
CC       undergo proper embryonic elongation. RNAi-mediated knockdown at the L1
CC       larval stage reduces survival (PubMed:30965033).
CC       {ECO:0000269|PubMed:30965033, ECO:0000269|PubMed:7607089}.
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DR   EMBL; U51163; AAA96319.1; -; Genomic_DNA.
DR   EMBL; BX284605; CAB07378.1; -; Genomic_DNA.
DR   EMBL; BX284605; CAK12559.1; -; Genomic_DNA.
DR   EMBL; BX284605; CAK12560.1; -; Genomic_DNA.
DR   PIR; T21941; T21941.
DR   RefSeq; NP_001041114.1; NM_001047649.2. [Q17381-1]
DR   RefSeq; NP_001041115.1; NM_001047650.2. [Q17381-2]
DR   RefSeq; NP_001041116.1; NM_001047651.3. [Q17381-3]
DR   AlphaFoldDB; Q17381; -.
DR   SMR; Q17381; -.
DR   BioGRID; 45314; 91.
DR   DIP; DIP-27474N; -.
DR   IntAct; Q17381; 74.
DR   STRING; 6239.F38A6.1a.1; -.
DR   EPD; Q17381; -.
DR   PaxDb; 6239-F38A6-1a; -.
DR   PeptideAtlas; Q17381; -.
DR   EnsemblMetazoa; F38A6.1a.1; F38A6.1a.1; WBGene00004013. [Q17381-1]
DR   EnsemblMetazoa; F38A6.1b.1; F38A6.1b.1; WBGene00004013. [Q17381-2]
DR   EnsemblMetazoa; F38A6.1c.1; F38A6.1c.1; WBGene00004013. [Q17381-3]
DR   GeneID; 180357; -.
DR   KEGG; cel:CELE_F38A6.1; -.
DR   UCSC; F38A6.1a; c. elegans. [Q17381-1]
DR   AGR; WB:WBGene00004013; -.
DR   WormBase; F38A6.1a; CE15998; WBGene00004013; pha-4. [Q17381-1]
DR   WormBase; F38A6.1b; CE40228; WBGene00004013; pha-4. [Q17381-2]
DR   WormBase; F38A6.1c; CE40229; WBGene00004013; pha-4. [Q17381-3]
DR   eggNOG; KOG3563; Eukaryota.
DR   GeneTree; ENSGT00940000155999; -.
DR   InParanoid; Q17381; -.
DR   OMA; YYTSNYM; -.
DR   OrthoDB; 2882520at2759; -.
DR   PhylomeDB; Q17381; -.
DR   SignaLink; Q17381; -.
DR   PRO; PR:Q17381; -.
DR   Proteomes; UP000001940; Chromosome V.
DR   Bgee; WBGene00004013; Expressed in pharyngeal muscle cell (C elegans) and 16 other cell types or tissues.
DR   GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR   GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IMP:WormBase.
DR   GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:UniProtKB.
DR   GO; GO:0043565; F:sequence-specific DNA binding; IDA:WormBase.
DR   GO; GO:0009653; P:anatomical structure morphogenesis; IBA:GO_Central.
DR   GO; GO:0030154; P:cell differentiation; IMP:WormBase.
DR   GO; GO:0060573; P:cell fate specification involved in pattern specification; IMP:WormBase.
DR   GO; GO:0008340; P:determination of adult lifespan; IGI:WormBase.
DR   GO; GO:0048598; P:embryonic morphogenesis; IMP:WormBase.
DR   GO; GO:0060465; P:pharynx development; IMP:WormBase.
DR   GO; GO:0016239; P:positive regulation of macroautophagy; IMP:WormBase.
DR   GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:UniProtKB.
DR   GO; GO:0045727; P:positive regulation of translation; IMP:WormBase.
DR   GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR   GO; GO:0061771; P:response to caloric restriction; IDA:UniProtKB.
DR   GO; GO:1903935; P:response to sodium arsenite; IMP:UniProtKB.
DR   CDD; cd20015; FH_FOXA; 1.
DR   Gene3D; 1.10.10.10; Winged helix-like DNA-binding domain superfamily/Winged helix DNA-binding domain; 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   PANTHER; PTHR11829:SF382; DEFECTIVE PHARYNGEAL DEVELOPMENT PROTEIN 4; 1.
DR   PANTHER; PTHR11829; FORKHEAD BOX PROTEIN; 1.
DR   Pfam; PF00250; Forkhead; 1.
DR   PRINTS; PR00053; FORKHEAD.
DR   SMART; SM00339; FH; 1.
DR   SUPFAM; SSF46785; Winged helix' DNA-binding domain; 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   Activator; Alternative splicing; Coiled coil; Developmental protein;
KW   DNA-binding; Nucleus; Reference proteome; Repressor; Transcription;
KW   Transcription regulation.
FT   CHAIN           1..506
FT                   /note="Defective pharyngeal development protein 4"
FT                   /id="PRO_0000294935"
FT   DNA_BIND        236..330
FT                   /note="Fork-head"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00089"
FT   REGION          1..88
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          184..210
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          332..366
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COILED          38..66
FT                   /evidence="ECO:0000255"
FT   COMPBIAS        41..65
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        66..88
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   VAR_SEQ         1..95
FT                   /note="Missing (in isoform c)"
FT                   /evidence="ECO:0000303|PubMed:8812130"
FT                   /id="VSP_052483"
FT   VAR_SEQ         1..64
FT                   /note="Missing (in isoform b)"
FT                   /evidence="ECO:0000303|PubMed:8812130"
FT                   /id="VSP_052482"
FT   MUTAGEN         158
FT                   /note="L->F: In q400; induces embryonic developmental
FT                   arrest and lack of a pharynx."
FT                   /evidence="ECO:0000269|PubMed:16127716"
SQ   SEQUENCE   506 AA;  55427 MW;  B9AF5D1A846F2A5E CRC64;
     MTSPSSDEDI IDIRVIKEEP ESEPDSEAEP ATTTNSTDSE DSVEQENKKL LETEKNRKRE
     QKHKMLPNGT TSGTSDTGNQ VPATSSAASS VDYTAMNAQD YLPTYSNTTL NYQPYQYQTA
     ANGLLNYNNY SQYATANQLG SNYISPANFM QGGGISPLGF TTGTTGATTA AASVATSSAS
     AVIGRSNGRS SSTVAASPAD RSYSGVSGGQ GQELTIQEFE TVTEKIRRHG TYGQSKPPYS
     YISLITMAIQ KSNSRQLTLS EIYNWIMDLF PYYQNNQQRW QNSIRHSLSF NDCFVKVARS
     PDKPGKGSFW TLHEHCGNMF ENGCYLRRQK RFKVKEREPS RKKRNANSQQ LHQQQHIPKM
     EIKEEDPTSI TTTSSLGAYS LIPQISTKKE IKEELKAVQD ATAAAANLGL IDPSGTPSAV
     NHSQPTSVIS SVGTLGTTQA QMTLNGQYAS PYLYSSDFAT ILPQSQNFLN NTLYNTTSSY
     PGIDYTNGVY QNTLYSSTNP NSAANL
//