PHA4_CAEEL
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 03-AUG-2022, entry version 174.
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; -.
DR EPD; Q17381; -.
DR PaxDb; Q17381; -.
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 CTD; 180357; -.
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; 1270467at2759; -.
DR PhylomeDB; Q17381; -.
DR Reactome; R-CEL-9018519; Estrogen-dependent gene expression.
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 tissues.
DR GO; GO:0005634; C:nucleus; IDA:WormBase.
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; IBA:GO_Central.
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; IMP:WormBase.
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; 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 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
