ID ID2_HUMAN Reviewed; 134 AA. AC Q02363; DT 01-FEB-1995, integrated into UniProtKB/Swiss-Prot. DT 01-FEB-1995, sequence version 1. DT 27-MAR-2024, entry version 201. DE RecName: Full=DNA-binding protein inhibitor ID-2; DE AltName: Full=Class B basic helix-loop-helix protein 26; DE Short=bHLHb26; DE AltName: Full=Inhibitor of DNA binding 2; DE AltName: Full=Inhibitor of differentiation 2; GN Name=ID2; Synonyms=BHLHB26; 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]. RC TISSUE=Lung; RX PubMed=8294468; DOI=10.1016/s0021-9258(17)42146-6; RA Hara E., Yamaguchi T., Nojima H., Ide T., Campisi J., Okayama H., Oda K.; RT "Id-related genes encoding helix-loop-helix proteins are required for G1 RT progression and are repressed in senescent human fibroblasts."; RL J. Biol. Chem. 269:2139-2145(1994). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=1741406; DOI=10.1073/pnas.89.4.1512; RA Biggs J., Murphy E.V., Israel M.A.; RT "A human Id-like helix-loop-helix protein expressed during early RT development."; RL Proc. Natl. Acad. Sci. U.S.A. 89:1512-1516(1992). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Hippocampus; 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 INTERACTION WITH NEDD9. RX PubMed=10502414; DOI=10.1006/excr.1999.4609; RA Law S.F., Zhang Y.-Z., Fashena S.J., Toby G., Estojak J., Golemis E.A.; RT "Dimerization of the docking/adaptor protein HEF1 via a carboxy-terminal RT helix-loop-helix domain."; RL Exp. Cell Res. 252:224-235(1999). RN [5] RP INTERACTION WITH NR0B2. RX PubMed=14752053; DOI=10.1210/me.2003-0311; RA Kim J.Y., Chu K., Kim H.J., Seong H.A., Park K.C., Sanyal S., Takeda J., RA Ha H., Shong M., Tsai M.J., Choi H.S.; RT "Orphan nuclear receptor small heterodimer partner, a novel corepressor for RT a basic helix-loop-helix transcription factor BETA2/neuroD."; RL Mol. Endocrinol. 18:776-790(2004). RN [6] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH CLOCK AND BMAL1. RX PubMed=20861012; DOI=10.1074/jbc.m110.175182; RA Ward S.M., Fernando S.J., Hou T.Y., Duffield G.E.; RT "The transcriptional repressor ID2 can interact with the canonical clock RT components CLOCK and BMAL1 and mediate inhibitory effects on mPer1 RT expression."; RL J. Biol. Chem. 285:38987-39000(2010). RN [7] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-14, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; 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 [8] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-14, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). CC -!- FUNCTION: Transcriptional regulator (lacking a basic DNA binding CC domain) which negatively regulates the basic helix-loop-helix (bHLH) CC transcription factors by forming heterodimers and inhibiting their DNA CC binding and transcriptional activity. Implicated in regulating a CC variety of cellular processes, including cellular growth, senescence, CC differentiation, apoptosis, angiogenesis, and neoplastic CC transformation. Inhibits skeletal muscle and cardiac myocyte CC differentiation. Regulates the circadian clock by repressing the CC transcriptional activator activity of the CLOCK-BMAL1 heterodimer. CC Restricts the CLOCK and BMAL1 localization to the cytoplasm. Plays a CC role in both the input and output pathways of the circadian clock: in CC the input component, is involved in modulating the magnitude of photic CC entrainment and in the output component, contributes to the regulation CC of a variety of liver clock-controlled genes involved in lipid CC metabolism. {ECO:0000269|PubMed:20861012}. CC -!- SUBUNIT: Interacts with GATA4 and NKX2-5 (By similarity). Interacts CC with NR0B2 (PubMed:14752053). Interacts with CLOCK and BMAL1 CC (PubMed:20861012). Interacts with IFI204 (By similarity). Interacts CC with NEDD9/HEF1 (PubMed:10502414). {ECO:0000250|UniProtKB:P41136, CC ECO:0000269|PubMed:10502414, ECO:0000269|PubMed:14752053, CC ECO:0000269|PubMed:20861012}. CC -!- INTERACTION: CC Q02363; Q6XD76: ASCL4; NbExp=3; IntAct=EBI-713450, EBI-10254793; CC Q02363; Q6P5X5: C22orf39; NbExp=3; IntAct=EBI-713450, EBI-7317823; CC Q02363; O95273: CCNDBP1; NbExp=4; IntAct=EBI-713450, EBI-748961; CC Q02363; Q9H0I2: ENKD1; NbExp=3; IntAct=EBI-713450, EBI-744099; CC Q02363; Q9NW38: FANCL; NbExp=3; IntAct=EBI-713450, EBI-2339898; CC Q02363; P11362-2: FGFR1; NbExp=3; IntAct=EBI-713450, EBI-25852941; CC Q02363; Q9BVV2: FNDC11; NbExp=3; IntAct=EBI-713450, EBI-744935; CC Q02363; O43559: FRS3; NbExp=3; IntAct=EBI-713450, EBI-725515; CC Q02363; Q5SUL5: HLA-A; NbExp=3; IntAct=EBI-713450, EBI-8561769; CC Q02363; O43464: HTRA2; NbExp=3; IntAct=EBI-713450, EBI-517086; CC Q02363; P42858: HTT; NbExp=6; IntAct=EBI-713450, EBI-466029; CC Q02363; Q92993: KAT5; NbExp=3; IntAct=EBI-713450, EBI-399080; CC Q02363; Q8TAP4-4: LMO3; NbExp=3; IntAct=EBI-713450, EBI-11742507; CC Q02363; A6NI15: MSGN1; NbExp=3; IntAct=EBI-713450, EBI-11991020; CC Q02363; Q96HC4: PDLIM5; NbExp=5; IntAct=EBI-713450, EBI-751267; CC Q02363; Q9NRD5: PICK1; NbExp=3; IntAct=EBI-713450, EBI-79165; CC Q02363; Q13563: PKD2; NbExp=7; IntAct=EBI-713450, EBI-7813714; CC Q02363; D3DTS7: PMP22; NbExp=3; IntAct=EBI-713450, EBI-25882629; CC Q02363; P62937-2: PPIA; NbExp=3; IntAct=EBI-713450, EBI-25884072; CC Q02363; P23284: PPIB; NbExp=3; IntAct=EBI-713450, EBI-359252; CC Q02363; P17252: PRKCA; NbExp=3; IntAct=EBI-713450, EBI-1383528; CC Q02363; Q15047-2: SETDB1; NbExp=3; IntAct=EBI-713450, EBI-9090795; CC Q02363; Q13148: TARDBP; NbExp=6; IntAct=EBI-713450, EBI-372899; CC Q02363; Q99081: TCF12; NbExp=2; IntAct=EBI-713450, EBI-722877; CC Q02363; P15923-1: TCF3; NbExp=3; IntAct=EBI-713450, EBI-769645; CC Q02363; P15884: TCF4; NbExp=3; IntAct=EBI-713450, EBI-533224; CC Q02363; Q9BT92: TCHP; NbExp=3; IntAct=EBI-713450, EBI-740781; CC Q02363; P61981: YWHAG; NbExp=3; IntAct=EBI-713450, EBI-359832; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:P41136}. Nucleus CC {ECO:0000250|UniProtKB:P41136}. CC -!- TISSUE SPECIFICITY: Highly expressed in early fetal tissues, including CC those of the central nervous system. CC -!- DEVELOPMENTAL STAGE: Found in most early fetal tissues but not in the CC corresponding mature tissues. CC -!- DOMAIN: The bHLH domain is essential for its repressor activity towards CC the CLOCK-BMAL1 heterodimer. {ECO:0000250}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; D13891; BAA02990.1; -; mRNA. DR EMBL; M97796; AAA58681.1; -; mRNA. DR EMBL; BC030639; AAH30639.1; -; mRNA. DR CCDS; CCDS1659.1; -. DR PIR; A40227; A40227. DR PIR; JC2007; JC2007. DR RefSeq; NP_002157.2; NM_002166.4. DR PDB; 4AYA; X-ray; 2.10 A; A/B=1-82. DR PDBsum; 4AYA; -. DR AlphaFoldDB; Q02363; -. DR BMRB; Q02363; -. DR SMR; Q02363; -. DR BioGRID; 109624; 94. DR DIP; DIP-46874N; -. DR ELM; Q02363; -. DR IntAct; Q02363; 62. DR MINT; Q02363; -. DR STRING; 9606.ENSP00000234091; -. DR GlyGen; Q02363; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q02363; -. DR PhosphoSitePlus; Q02363; -. DR BioMuta; ID2; -. DR DMDM; 729806; -. DR jPOST; Q02363; -. DR MassIVE; Q02363; -. DR PaxDb; 9606-ENSP00000234091; -. DR PeptideAtlas; Q02363; -. DR ProteomicsDB; 58083; -. DR Pumba; Q02363; -. DR Antibodypedia; 12350; 503 antibodies from 38 providers. DR DNASU; 3398; -. DR Ensembl; ENST00000234091.8; ENSP00000234091.4; ENSG00000115738.10. DR Ensembl; ENST00000331129.3; ENSP00000385465.2; ENSG00000115738.10. DR Ensembl; ENST00000396290.2; ENSP00000379585.1; ENSG00000115738.10. DR GeneID; 3398; -. DR KEGG; hsa:3398; -. DR MANE-Select; ENST00000396290.2; ENSP00000379585.1; NM_002166.5; NP_002157.2. DR AGR; HGNC:5361; -. DR CTD; 3398; -. DR DisGeNET; 3398; -. DR GeneCards; ID2; -. DR HGNC; HGNC:5361; ID2. DR HPA; ENSG00000115738; Tissue enhanced (parathyroid). DR MIM; 600386; gene. DR neXtProt; NX_Q02363; -. DR OpenTargets; ENSG00000115738; -. DR PharmGKB; PA29609; -. DR VEuPathDB; HostDB:ENSG00000115738; -. DR eggNOG; ENOG502RZP5; Eukaryota. DR GeneTree; ENSGT00940000156464; -. DR HOGENOM; CLU_116790_2_1_1; -. DR InParanoid; Q02363; -. DR OMA; SFRKNGA; -. DR OrthoDB; 4207391at2759; -. DR PhylomeDB; Q02363; -. DR TreeFam; TF326217; -. DR PathwayCommons; Q02363; -. DR Reactome; R-HSA-9031628; NGF-stimulated transcription. DR SignaLink; Q02363; -. DR SIGNOR; Q02363; -. DR BioGRID-ORCS; 3398; 26 hits in 1147 CRISPR screens. DR ChiTaRS; ID2; human. DR GeneWiki; ID2; -. DR GenomeRNAi; 3398; -. DR Pharos; Q02363; Tbio. DR PRO; PR:Q02363; -. DR Proteomes; UP000005640; Chromosome 2. DR RNAct; Q02363; Protein. DR Bgee; ENSG00000115738; Expressed in popliteal artery and 207 other cell types or tissues. DR ExpressionAtlas; Q02363; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:BHF-UCL. DR GO; GO:0000791; C:euchromatin; ISS:ARUK-UCL. DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome. DR GO; GO:0005634; C:nucleus; IDA:BHF-UCL. DR GO; GO:0032991; C:protein-containing complex; ISS:UniProtKB. DR GO; GO:0046983; F:protein dimerization activity; IEA:InterPro. DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; ISS:ARUK-UCL. DR GO; GO:0140416; F:transcription regulator inhibitor activity; ISS:ARUK-UCL. DR GO; GO:0044325; F:transmembrane transporter binding; IPI:BHF-UCL. DR GO; GO:0003166; P:bundle of His development; ISS:BHF-UCL. DR GO; GO:0030154; P:cell differentiation; IBA:GO_Central. DR GO; GO:0090398; P:cellular senescence; ISS:UniProtKB. DR GO; GO:0032922; P:circadian regulation of gene expression; ISS:UniProtKB. DR GO; GO:0007623; P:circadian rhythm; ISS:ARUK-UCL. DR GO; GO:0048557; P:embryonic digestive tract morphogenesis; ISS:UniProtKB. DR GO; GO:0061031; P:endodermal digestive tract morphogenesis; ISS:UniProtKB. DR GO; GO:0043153; P:entrainment of circadian clock by photoperiod; ISS:UniProtKB. DR GO; GO:0043353; P:enucleate erythrocyte differentiation; ISS:ARUK-UCL. DR GO; GO:0061030; P:epithelial cell differentiation involved in mammary gland alveolus development; ISS:UniProtKB. DR GO; GO:0007507; P:heart development; ISS:BHF-UCL. DR GO; GO:0045475; P:locomotor rhythm; ISS:UniProtKB. DR GO; GO:0060749; P:mammary gland alveolus development; ISS:UniProtKB. DR GO; GO:0033598; P:mammary gland epithelial cell proliferation; ISS:UniProtKB. DR GO; GO:0045578; P:negative regulation of B cell differentiation; ISS:ARUK-UCL. DR GO; GO:0043433; P:negative regulation of DNA-binding transcription factor activity; IDA:GDB. DR GO; GO:0045892; P:negative regulation of DNA-templated transcription; IDA:GDB. DR GO; GO:0010629; P:negative regulation of gene expression; ISS:UniProtKB. DR GO; GO:0051148; P:negative regulation of muscle cell differentiation; ISS:BHF-UCL. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISS:ARUK-UCL. DR GO; GO:0048663; P:neuron fate commitment; ISS:UniProtKB. DR GO; GO:0021772; P:olfactory bulb development; ISS:ARUK-UCL. DR GO; GO:0048711; P:positive regulation of astrocyte differentiation; ISS:ARUK-UCL. DR GO; GO:0045777; P:positive regulation of blood pressure; ISS:UniProtKB. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; ISS:UniProtKB. DR GO; GO:0045600; P:positive regulation of fat cell differentiation; ISS:ARUK-UCL. DR GO; GO:0010628; P:positive regulation of gene expression; ISS:UniProtKB. DR GO; GO:0045651; P:positive regulation of macrophage differentiation; ISS:ARUK-UCL. DR GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; ISS:UniProtKB. DR GO; GO:0042752; P:regulation of circadian rhythm; ISS:UniProtKB. DR GO; GO:2000045; P:regulation of G1/S transition of mitotic cell cycle; IMP:BHF-UCL. DR GO; GO:0019216; P:regulation of lipid metabolic process; ISS:UniProtKB. DR GO; GO:2000177; P:regulation of neural precursor cell proliferation; ISS:UniProtKB. DR GO; GO:0045664; P:regulation of neuron differentiation; ISS:UniProtKB. DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IMP:BHF-UCL. DR CDD; cd19692; bHLH_dnHLH_ID2; 1. DR DisProt; DP02697; -. DR Gene3D; 4.10.280.10; Helix-loop-helix DNA-binding domain; 1. DR InterPro; IPR011598; bHLH_dom. DR InterPro; IPR026052; DNA-bd_prot-inh. DR InterPro; IPR036638; HLH_DNA-bd_sf. DR PANTHER; PTHR11723; DNA-BINDING PROTEIN INHIBITOR; 1. DR PANTHER; PTHR11723:SF5; DNA-BINDING PROTEIN INHIBITOR ID-2; 1. DR Pfam; PF00010; HLH; 1. DR SMART; SM00353; HLH; 1. DR SUPFAM; SSF47459; HLH, helix-loop-helix DNA-binding domain; 1. DR PROSITE; PS50888; BHLH; 1. DR Genevisible; Q02363; HS. PE 1: Evidence at protein level; KW 3D-structure; Biological rhythms; Cytoplasm; Developmental protein; KW Nucleus; Phosphoprotein; Reference proteome; Repressor; Transcription; KW Transcription regulation. FT CHAIN 1..134 FT /note="DNA-binding protein inhibitor ID-2" FT /id="PRO_0000127240" FT DOMAIN 23..75 FT /note="bHLH" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00981" FT MOTIF 106..115 FT /note="Nuclear export signal" FT /evidence="ECO:0000250" FT MOD_RES 14 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163, FT ECO:0007744|PubMed:24275569" FT MOD_RES 25 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P41136" FT CONFLICT 68 FT /note="V -> L (in Ref. 2; AAA58681)" FT /evidence="ECO:0000305" FT CONFLICT 98 FT /note="A -> R (in Ref. 2; AAA58681)" FT /evidence="ECO:0000305" FT HELIX 32..49 FT /evidence="ECO:0007829|PDB:4AYA" FT STRAND 55..57 FT /evidence="ECO:0007829|PDB:4AYA" FT HELIX 61..80 FT /evidence="ECO:0007829|PDB:4AYA" SQ SEQUENCE 134 AA; 14917 MW; A0D98B96396EB11E CRC64; MKAFSPVRSV RKNSLSDHSL GISRSKTPVD DPMSLLYNMN DCYSKLKELV PSIPQNKKVS KMEILQHVID YILDLQIALD SHPTIVSLHH QRPGQNQASR TPLTTLNTDI SILSLQASEF PSELMSNDSK ALCG //