HLH2_CAEEL
ID HLH2_CAEEL Reviewed; 399 AA.
AC G5EEG9; Q17326; Q17358;
DT 29-SEP-2021, integrated into UniProtKB/Swiss-Prot.
DT 14-DEC-2011, sequence version 1.
DT 03-AUG-2022, entry version 78.
DE RecName: Full=Helix-loop-helix protein hlh-2 {ECO:0000312|WormBase:M05B5.5a};
GN Name=hlh-2 {ECO:0000312|WormBase:M05B5.5a};
GN ORFNames=M05B5.5 {ECO:0000312|WormBase:M05B5.5a};
OS Caenorhabditis elegans.
OC Eukaryota; Metazoa; Ecdysozoa; Nematoda; Chromadorea; Rhabditida;
OC Rhabditina; Rhabditomorpha; Rhabditoidea; Rhabditidae; Peloderinae;
OC Caenorhabditis.
OX NCBI_TaxID=6239 {ECO:0000312|Proteomes:UP000001940};
RN [1] {ECO:0000312|EMBL:AAA21347.1, ECO:0000312|EMBL:AAC13874.1}
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
RC STRAIN=Bristol N2 {ECO:0000312|EMBL:AAA21347.1,
RC ECO:0000312|EMBL:AAC13874.1};
RA Krause M.W., Fire A.;
RT "cDNA sequence of the C. elegans homolog of the vertebrate basic-helix-
RT loop-helix transcription factor, E12/47.";
RL Submitted (AUG-1994) to the EMBL/GenBank/DDBJ databases.
RN [2] {ECO:0000312|Proteomes:UP000001940}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Bristol N2 {ECO:0000312|Proteomes:UP000001940};
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, INTERACTION WITH LIN-32, SUBCELLULAR LOCATION, DEVELOPMENTAL
RP STAGE, AND MUTAGENESIS OF ARG-316 AND VAL-352.
RX PubMed=11076762; DOI=10.1242/dev.127.24.5415;
RA Portman D.S., Emmons S.W.;
RT "The basic helix-loop-helix transcription factors LIN-32 and HLH-2 function
RT together in multiple steps of a C. elegans neuronal sublineage.";
RL Development 127:5415-5426(2000).
RN [4] {ECO:0000305}
RP FUNCTION, DEVELOPMENTAL STAGE, AND DISRUPTION PHENOTYPE.
RX PubMed=14701877; DOI=10.1101/gad.1160803;
RA Karp X., Greenwald I.;
RT "Post-transcriptional regulation of the E/Daughterless ortholog HLH-2,
RT negative feedback, and birth order bias during the AC/VU decision in C.
RT elegans.";
RL Genes Dev. 17:3100-3111(2003).
RN [5] {ECO:0000305}
RP FUNCTION, INTERACTION WITH HLH-12, AND DISRUPTION PHENOTYPE.
RX PubMed=17588558; DOI=10.1016/j.ydbio.2007.05.024;
RA Tamai K.K., Nishiwaki K.;
RT "bHLH transcription factors regulate organ morphogenesis via activation of
RT an ADAMTS protease in C. elegans.";
RL Dev. Biol. 308:562-571(2007).
RN [6] {ECO:0000305}
RP FUNCTION, INTERACTION WITH HLH-10, AND DEVELOPMENTAL STAGE.
RX PubMed=19632181; DOI=10.1016/j.cell.2009.04.058;
RA Grove C.A., De Masi F., Barrasa M.I., Newburger D.E., Alkema M.J.,
RA Bulyk M.L., Walhout A.J.M.;
RT "A multiparameter network reveals extensive divergence between C. elegans
RT bHLH transcription factors.";
RL Cell 138:314-327(2009).
RN [7] {ECO:0000305}
RP FUNCTION, DEVELOPMENTAL STAGE, AND DISRUPTION PHENOTYPE.
RX PubMed=19376107; DOI=10.1016/j.ydbio.2009.04.015;
RA Chesney M.A., Lam N., Morgan D.E., Phillips B.T., Kimble J.;
RT "C. elegans HLH-2/E/Daughterless controls key regulatory cells during
RT gonadogenesis.";
RL Dev. Biol. 331:14-25(2009).
RN [8] {ECO:0000305}
RP FUNCTION, INTERACTION WITH NGN-1, DEVELOPMENTAL STAGE, AND DISRUPTION
RP PHENOTYPE.
RX PubMed=21041366; DOI=10.1242/dev.058834;
RA Nakano S., Ellis R.E., Horvitz H.R.;
RT "Otx-dependent expression of proneural bHLH genes establishes a neuronal
RT bilateral asymmetry in C. elegans.";
RL Development 137:4017-4027(2010).
RN [9] {ECO:0000305}
RP FUNCTION, DEVELOPMENTAL STAGE, AND DISRUPTION PHENOTYPE.
RX PubMed=21784067; DOI=10.1016/j.ydbio.2011.07.012;
RA Schindler A.J., Sherwood D.R.;
RT "The transcription factor HLH-2/E/Daughterless regulates anchor cell
RT invasion across basement membrane in C. elegans.";
RL Dev. Biol. 357:380-391(2011).
RN [10] {ECO:0000305}
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=25982859; DOI=10.1016/j.gene.2015.05.030;
RA Meighan C.M., Kann A.P., Egress E.R.;
RT "Transcription factor hlh-2/E/Daughterless drives expression of alpha
RT integrin ina-1 during DTC migration in C. elegans.";
RL Gene 568:220-226(2015).
RN [11] {ECO:0000305}
RP FUNCTION, AND DEVELOPMENTAL STAGE.
RX PubMed=31402303; DOI=10.1016/j.cub.2019.07.062;
RA Attner M.A., Keil W., Benavidez J.M., Greenwald I.;
RT "HLH-2/E2A Expression Links Stochastic and Deterministic Elements of a Cell
RT Fate Decision during C. elegans Gonadogenesis.";
RL Curr. Biol. 29:3094-3100(2019).
RN [12] {ECO:0000305}
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=32203922; DOI=10.1016/j.redox.2020.101448;
RA Rozanov L., Ravichandran M., Grigolon G., Zanellati M.C., Mansfeld J.,
RA Zarse K., Barzilai N., Atzmon G., Fischer F., Ristow M.;
RT "Redox-mediated regulation of aging and healthspan by an evolutionarily
RT conserved transcription factor HLH-2/Tcf3/E2A.";
RL Redox Biol. 32:101448-101448(2020).
CC -!- FUNCTION: Transcription factor which binds the E box motif 5'-
CC CA[TC][AG]TG-3' (PubMed:19632181, PubMed:11076762, PubMed:14701877).
CC Plays a key role in the anchor cell/ventral uterine precursor cell
CC (AC/VU) decision; required for VU fate (PubMed:14701877,
CC PubMed:31402303). Regulates expression of lin-12/Notch receptor and
CC putative ligand lag-2 in the presumptive AC and presumptive VU cells
CC (PubMed:31402303). Modulates expression of lag-2 in the gonadal distal
CC tip cells (DTCs) (PubMed:14701877, PubMed:19376107). Involved in
CC formation of the polarised cell membrane of the AC and thus facilitates
CC invasion across the gonadal basement membrane, acting via
CC transcriptional modulation of multiple genes (PubMed:21784067).
CC Involved in specification of the hermaphrodite DTC and the male linker
CC cell, perhaps acting in concert with the homeobox protein, ceh-22
CC (PubMed:19376107). Plays a role in regulation of migration of DTCs and
CC the modulation of expression of alpha integrin ina-1 and ADAMTS
CC protease gon-1 (PubMed:25982859, PubMed:17588558). Required for DTC
CC maintenance, and for function of the DTC as a niche for germline stem
CC cells (PubMed:19376107). Plays a role in cell-autonomously establishing
CC a neuronal left-right asymmetry (PubMed:21041366). Required for
CC specification of cell fate, acting in concert with lin-32, in the
CC development of the male-specific genital sensilla (simple sense organs)
CC known as rays (PubMed:11076762). Negatively modulates lifespan, perhaps
CC acting by regulating expression of arginine kinases, which in turn
CC results in altered metabolism and homeostasis of reactive oxygen
CC species (ROS) (PubMed:32203922). {ECO:0000269|PubMed:11076762,
CC ECO:0000269|PubMed:14701877, ECO:0000269|PubMed:17588558,
CC ECO:0000269|PubMed:19376107, ECO:0000269|PubMed:19632181,
CC ECO:0000269|PubMed:21041366, ECO:0000269|PubMed:21784067,
CC ECO:0000269|PubMed:25982859, ECO:0000269|PubMed:31402303,
CC ECO:0000269|PubMed:32203922}.
CC -!- SUBUNIT: Interacts with helix-loop-helix protein ngn-1; the interaction
CC is direct (PubMed:21041366). Efficient DNA binding probably requires
CC dimerization with another helix-loop-helix protein (PubMed:19632181,
CC PubMed:11076762). Forms a heterodimer with helix-loop-helix protein
CC hlh-12 (PubMed:17588558). Forms a heterodimer with lin-32
CC (PubMed:11076762). May form a heterodimer with hlh-10
CC (PubMed:19632181). {ECO:0000269|PubMed:11076762,
CC ECO:0000269|PubMed:17588558, ECO:0000269|PubMed:19632181,
CC ECO:0000269|PubMed:21041366}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:11076762}.
CC -!- DEVELOPMENTAL STAGE: During male tail development, expressed in each of
CC the nine Rn cells and in the anterior daughter cell, the ray neuroblast
CC (at protein level) (PubMed:11076762). First expressed at the comma
CC stage of embryogenesis (PubMed:19632181). Expressed asymmetrically, in
CC the mother cell of the MI pharyngeal motorneuron but not in the mother
CC cell of the e3D epithelial cell (PubMed:21041366). Expressed during
CC hermaphrodite gonadogenesis, in the two somatic gonadal progenitor
CC (SGP) cells, Z1.ppp and Z4.aaa, precursors to the anchor cell (AC) and
CC the ventral uterine precursor cell (VU), but not detected in their
CC sister cells, Z1.ppa and Z4.aap (PubMed:14701877, PubMed:19376107,
CC PubMed:21784067). Expressed in both pre-AC and pre-VU cells, and after
CC the AC/VU decision, expression is reduced in the VU and its
CC descendants; however, expression persists in the AC through the time of
CC basement membrane invasion (PubMed:21784067, PubMed:31402303).
CC Expressed in the gonadal distal tip cells (DTCs) throughout development
CC and in adults (PubMed:19376107). {ECO:0000269|PubMed:11076762,
CC ECO:0000269|PubMed:14701877, ECO:0000269|PubMed:19376107,
CC ECO:0000269|PubMed:19632181, ECO:0000269|PubMed:21041366,
CC ECO:0000269|PubMed:21784067, ECO:0000269|PubMed:31402303}.
CC -!- DISRUPTION PHENOTYPE: RNAi-mediated knockdown in the early larval L1
CC stage causes both somatic gonadal progenitor (SGP) cells, Z1.ppp and
CC Z4.aaa, to assume the ventral uterine precursor cell (VU) identity;
CC whereas, if RNAi is applied during the late larval L1 stage, or at the
CC larval L2 stage, both assume the anchor cell (AC) identity
CC (PubMed:21784067, PubMed:14701877). RNAi-mediated knockdown applied at
CC the time of the larval stage L1/L2 molt causes defects in invasion of
CC the basement membrane by the AC (PubMed:21784067). RNAi-mediated
CC knockdown causes the MI pharyngeal motorneuron to transform into an
CC e3D-like epithelial cell (PubMed:21041366). RNAi-mediated knockdown
CC reduces expression of alpha integrin ina-1 and of ADAMTS protease gon-
CC 1, and causes defects in migration of the gonadal distal tip cells
CC (DTCs) (PubMed:25982859, PubMed:17588558). RNAi-mediated knockdown
CC causes reduction in the number of hermaphrodites with DTCs, diminishes
CC formation of elongated gonadal arms and reduces expression of lag-2
CC (PubMed:19376107). RNAi-mediated knockdown during larval stage L3
CC causes a subsequent three-fold reduction in germ cell number in the
CC adult hermaphrodite gonad (PubMed:19376107). RNAi-mediated knockdown
CC increases lifespan, reduces fertility, improves the response to
CC proteotoxic stress, alters the response to reactive oxygen species
CC (ROS) and reduces expression of arginine kinases such as argk-1
CC (PubMed:32203922). {ECO:0000269|PubMed:14701877,
CC ECO:0000269|PubMed:17588558, ECO:0000269|PubMed:19376107,
CC ECO:0000269|PubMed:21041366, ECO:0000269|PubMed:21784067,
CC ECO:0000269|PubMed:25982859, ECO:0000269|PubMed:32203922}.
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DR EMBL; U13614; AAA21347.1; -; mRNA.
DR EMBL; U30248; AAC13874.1; -; Genomic_DNA.
DR EMBL; BX284601; CAA95837.1; -; Genomic_DNA.
DR PIR; T18853; T18853.
DR RefSeq; NP_001021581.1; NM_001026410.3.
DR AlphaFoldDB; G5EEG9; -.
DR SMR; G5EEG9; -.
DR IntAct; G5EEG9; 16.
DR STRING; 6239.M05B5.5a; -.
DR EPD; G5EEG9; -.
DR PaxDb; G5EEG9; -.
DR PeptideAtlas; G5EEG9; -.
DR EnsemblMetazoa; M05B5.5a.1; M05B5.5a.1; WBGene00001949.
DR GeneID; 172458; -.
DR KEGG; cel:CELE_M05B5.5; -.
DR CTD; 172458; -.
DR WormBase; M05B5.5a; CE06191; WBGene00001949; hlh-2.
DR eggNOG; KOG3910; Eukaryota.
DR GeneTree; ENSGT00940000168822; -.
DR HOGENOM; CLU_700646_0_0_1; -.
DR InParanoid; G5EEG9; -.
DR OMA; DAMSSMY; -.
DR OrthoDB; 1442255at2759; -.
DR PhylomeDB; G5EEG9; -.
DR Reactome; R-CEL-525793; Myogenesis.
DR Proteomes; UP000001940; Chromosome I.
DR Bgee; WBGene00001949; Expressed in embryo and 4 other tissues.
DR GO; GO:0005737; C:cytoplasm; IDA:WormBase.
DR GO; GO:0005634; C:nucleus; IDA:WormBase.
DR GO; GO:0090575; C:RNA polymerase II transcription regulator complex; IDA:WormBase.
DR GO; GO:0005667; C:transcription regulator complex; IBA:GO_Central.
DR GO; GO:0043425; F:bHLH transcription factor binding; IPI:WormBase.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IDA:WormBase.
DR GO; GO:0046982; F:protein heterodimerization activity; IPI:WormBase.
DR GO; GO:0042803; F:protein homodimerization activity; IPI:WormBase.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IMP:UniProtKB.
DR GO; GO:0000977; F:RNA polymerase II transcription regulatory region sequence-specific DNA binding; IDA:WormBase.
DR GO; GO:0043565; F:sequence-specific DNA binding; IDA:WormBase.
DR GO; GO:0046034; P:ATP metabolic process; IMP:UniProtKB.
DR GO; GO:0034769; P:basement membrane disassembly; IMP:UniProtKB.
DR GO; GO:0010171; P:body morphogenesis; IMP:WormBase.
DR GO; GO:0001708; P:cell fate specification; IMP:UniProtKB.
DR GO; GO:0008340; P:determination of adult lifespan; IMP:UniProtKB.
DR GO; GO:0009792; P:embryo development ending in birth or egg hatching; IMP:WormBase.
DR GO; GO:0030718; P:germ-line stem cell population maintenance; IMP:UniProtKB.
DR GO; GO:0008406; P:gonad development; IMP:WormBase.
DR GO; GO:0035262; P:gonad morphogenesis; IMP:UniProtKB.
DR GO; GO:0042743; P:hydrogen peroxide metabolic process; IMP:UniProtKB.
DR GO; GO:0002119; P:nematode larval development; IMP:WormBase.
DR GO; GO:0045138; P:nematode male tail tip morphogenesis; IMP:WormBase.
DR GO; GO:0014018; P:neuroblast fate specification; IMP:WormBase.
DR GO; GO:0048666; P:neuron development; IGI:WormBase.
DR GO; GO:0048665; P:neuron fate specification; IMP:UniProtKB.
DR GO; GO:1903356; P:positive regulation of distal tip cell migration; IMP:UniProtKB.
DR GO; GO:0010628; P:positive regulation of gene expression; IMP:UniProtKB.
DR GO; GO:0043068; P:positive regulation of programmed cell death; IMP:WormBase.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IMP:UniProtKB.
DR GO; GO:2000114; P:regulation of establishment of cell polarity; IMP:UniProtKB.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IDA:WormBase.
DR GO; GO:0000003; P:reproduction; IMP:WormBase.
DR GO; GO:1990636; P:reproductive senescence; IMP:UniProtKB.
DR GO; GO:0032094; P:response to food; IMP:UniProtKB.
DR GO; GO:0040025; P:vulval development; IMP:UniProtKB.
DR Gene3D; 4.10.280.10; -; 1.
DR InterPro; IPR011598; bHLH_dom.
DR InterPro; IPR036638; HLH_DNA-bd_sf.
DR Pfam; PF00010; HLH; 1.
DR SMART; SM00353; HLH; 1.
DR SUPFAM; SSF47459; SSF47459; 1.
DR PROSITE; PS50888; BHLH; 1.
PE 1: Evidence at protein level;
KW Developmental protein; DNA-binding; Neurogenesis; Nucleus;
KW Reference proteome; Transcription; Transcription regulation.
FT CHAIN 1..399
FT /note="Helix-loop-helix protein hlh-2"
FT /id="PRO_0000453281"
FT DOMAIN 302..356
FT /note="bHLH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00981"
FT REGION 66..119
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 208..315
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 302..315
FT /note="Basic motif"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00981"
FT REGION 316..356
FT /note="Helix-loop-helix motif"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00981"
FT REGION 371..399
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 248..291
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 292..315
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 372..386
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MUTAGEN 316
FT /note="R->H: In bx108; enhances the loss of male-specific
FT genital sensilla (simple sense organs) known as rays, on a
FT lin-32 mutant background. Slightly reduces binding to DNA
FT as a heterodimer with lin-32."
FT /evidence="ECO:0000269|PubMed:11076762"
FT MUTAGEN 352
FT /note="V->M: In bx115; enhances the loss of male-specific
FT genital sensilla (simple sense organs) known as rays, on a
FT lin-32 mutant background. Causes defects in all three ray
FT cell types. Slightly reduces binding to DNA as a
FT heterodimer with lin-32."
FT /evidence="ECO:0000269|PubMed:11076762"
FT CONFLICT 210
FT /note="Q -> P (in Ref. 1; AAA21347/AAC13874)"
FT /evidence="ECO:0000305"
FT CONFLICT 224
FT /note="N -> H (in Ref. 1; AAA21347/AAC13874)"
FT /evidence="ECO:0000305"
FT CONFLICT 347
FT /note="H -> Y (in Ref. 1; AAA21347/AAC13874)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 399 AA; 43193 MW; 8E139D03E597863B CRC64;
MADPNSQLTS ATTVATAAIA QPQVMLPNAY DYPYNIDPTT IQMPDYWSGY HLNPYPPMQT
TDIDYSSAFL PTHPPTETPA SVAAPTSATS DIKPIHATSS TSTTAPSTAP APTSTTDVLE
LKPTTAPATN SAETSAIVAP QPLTNLTAPI DAMSSMYTWP QTYPGYLPPS EDNKASEAVN
PYISIPPTYT FGADPSVADF SSYQQQLAGQ PNGLGGDTNL VDYNHQFPPA GMSPHFDPNG
YPGMTGMPPG SSASSVRNDK SASRATSRRR VQGPPSSGIP TRHSSSSRLS DNESMSDDKD
TDRRSQNNAR ERVRVRDINS AFKELGRMCT QHNQNTERNQ TKLGILHNAV SVITQLEEQV
RQRNMNPKVM AGMKRKPDDD KMKMLDDNAP SAQFGHPRF
