ID HAND2_HUMAN Reviewed; 217 AA. AC P61296; B6ECG9; O95300; O95301; P97833; Q494T1; DT 10-MAY-2004, integrated into UniProtKB/Swiss-Prot. DT 10-MAY-2004, sequence version 1. DT 09-APR-2025, entry version 162. DE RecName: Full=Heart- and neural crest derivatives-expressed protein 2; DE AltName: Full=Class A basic helix-loop-helix protein 26; DE Short=bHLHa26; DE AltName: Full=Deciduum, heart, autonomic nervous system and neural crest derivatives-expressed protein 2; DE Short=dHAND; GN Name=HAND2; Synonyms=BHLHA26, DHAND; 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 [GENOMIC DNA / MRNA] (ISOFORM 1). RC TISSUE=Embryonic heart; RX PubMed=9878849; DOI=10.1016/s0167-4781(98)00237-1; RA Russell M.W., Kemp P., Wang L., Brody L.C., Izumo S.; RT "Molecular cloning of the human HAND2 gene."; RL Biochim. Biophys. Acta 1443:393-399(1998). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Neuroblastoma; RX PubMed=19348682; DOI=10.1186/1471-2199-10-28; RA Voth H., Oberthuer A., Simon T., Kahlert Y., Berthold F., Fischer M.; RT "Co-regulated expression of HAND2 and DEIN by a bidirectional promoter with RT asymmetrical activity in neuroblastoma."; RL BMC Mol. Biol. 10:28-28(2009). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). 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). CC -!- FUNCTION: Essential for cardiac morphogenesis, particularly for the CC formation of the right ventricle and of the aortic arch arteries. CC Required for vascular development and regulation of angiogenesis, CC possibly through a VEGF signaling pathway. Also plays an important role CC in limb development, particularly in the establishment of anterior- CC posterior polarization, acting as an upstream regulator of sonic CC hedgehog (SHH) induction in the limb bud. Is involved in the CC development of branchial arches, which give rise to unique structures CC in the head and neck. Binds DNA on E-box consensus sequence 5'-CANNTG- CC 3' (By similarity). {ECO:0000250}. CC -!- SUBUNIT: Efficient DNA binding requires dimerization with another bHLH CC protein. Forms homodimers and heterodimers with TCF3 gene products E12 CC and E47, HAND1 and HEY1, HEY2 and HEYL (hairy-related transcription CC factors) (By similarity). {ECO:0000250}. CC -!- INTERACTION: CC P61296; P15884: TCF4; NbExp=4; IntAct=EBI-10218584, EBI-533224; CC P61296-2; Q86YD7: FAM90A1; NbExp=3; IntAct=EBI-13086076, EBI-6658203; CC P61296-2; Q63ZY3: KANK2; NbExp=3; IntAct=EBI-13086076, EBI-2556193; CC P61296-2; Q96CV9: OPTN; NbExp=3; IntAct=EBI-13086076, EBI-748974; CC P61296-2; Q0D2K3: RIPPLY1; NbExp=3; IntAct=EBI-13086076, EBI-10226430; CC P61296-2; Q5MJ09: SPANXN3; NbExp=3; IntAct=EBI-13086076, EBI-12037215; CC P61296-2; Q99081-3: TCF12; NbExp=3; IntAct=EBI-13086076, EBI-11952764; CC P61296-2; Q9Y2K6: USP20; NbExp=3; IntAct=EBI-13086076, EBI-2511991; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000255|PROSITE-ProRule:PRU00981}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=P61296-1; Sequence=Displayed; CC Name=2; CC IsoId=P61296-2; Sequence=VSP_056880, VSP_056881; CC -!- TISSUE SPECIFICITY: Heart. CC -!- DEVELOPMENTAL STAGE: Expressed in the fetal heart. 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; AF087940; AAD13185.1; -; mRNA. DR EMBL; AF087941; AAD13186.1; -; Genomic_DNA. DR EMBL; FJ226608; ACI42790.1; -; mRNA. DR EMBL; CH471056; EAX04749.1; -; Genomic_DNA. DR EMBL; BC101406; AAI01407.1; -; mRNA. DR CCDS; CCDS3819.1; -. [P61296-1] DR RefSeq; NP_068808.1; NM_021973.3. [P61296-1] DR AlphaFoldDB; P61296; -. DR SMR; P61296; -. DR BioGRID; 114850; 30. DR IntAct; P61296; 10. DR STRING; 9606.ENSP00000352565; -. DR iPTMnet; P61296; -. DR PhosphoSitePlus; P61296; -. DR BioMuta; HAND2; -. DR DMDM; 47117699; -. DR jPOST; P61296; -. DR MassIVE; P61296; -. DR PaxDb; 9606-ENSP00000352565; -. DR PeptideAtlas; P61296; -. DR ProteomicsDB; 57292; -. [P61296-1] DR Antibodypedia; 28534; 384 antibodies from 30 providers. DR DNASU; 9464; -. DR Ensembl; ENST00000359562.4; ENSP00000352565.4; ENSG00000164107.9. [P61296-1] DR GeneID; 9464; -. DR KEGG; hsa:9464; -. DR MANE-Select; ENST00000359562.4; ENSP00000352565.4; NM_021973.3; NP_068808.1. DR UCSC; uc003ith.2; human. [P61296-1] DR AGR; HGNC:4808; -. DR CTD; 9464; -. DR DisGeNET; 9464; -. DR GeneCards; HAND2; -. DR HGNC; HGNC:4808; HAND2. DR HPA; ENSG00000164107; Tissue enhanced (intestine). DR MalaCards; HAND2; -. DR MIM; 602407; gene. DR neXtProt; NX_P61296; -. DR OpenTargets; ENSG00000164107; -. DR Orphanet; 154; Familial isolated dilated cardiomyopathy. DR PharmGKB; PA29184; -. DR VEuPathDB; HostDB:ENSG00000164107; -. DR eggNOG; KOG4029; Eukaryota. DR GeneTree; ENSGT00940000160772; -. DR InParanoid; P61296; -. DR OMA; PDYGMAL; -. DR OrthoDB; 10055449at2759; -. DR PhylomeDB; P61296; -. DR TreeFam; TF315153; -. DR PathwayCommons; P61296; -. DR Reactome; R-HSA-8878166; Transcriptional regulation by RUNX2. DR Reactome; R-HSA-9733709; Cardiogenesis. DR SignaLink; P61296; -. DR SIGNOR; P61296; -. DR BioGRID-ORCS; 9464; 14 hits in 1174 CRISPR screens. DR ChiTaRS; HAND2; human. DR GeneWiki; HAND2; -. DR GenomeRNAi; 9464; -. DR Pharos; P61296; Tbio. DR PRO; PR:P61296; -. DR Proteomes; UP000005640; Chromosome 4. DR RNAct; P61296; protein. DR Bgee; ENSG00000164107; Expressed in muscle layer of sigmoid colon and 97 other cell types or tissues. DR ExpressionAtlas; P61296; baseline and differential. DR GO; GO:0000785; C:chromatin; IDA:BHF-UCL. DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell. DR GO; GO:0032991; C:protein-containing complex; IDA:UniProtKB. DR GO; GO:0005667; C:transcription regulator complex; ISS:BHF-UCL. DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IDA:UniProtKB. DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISS:BHF-UCL. DR GO; GO:0070888; F:E-box binding; IDA:UniProtKB. DR GO; GO:0003680; F:minor groove of adenine-thymine-rich DNA binding; IDA:UniProtKB. DR GO; GO:0042803; F:protein homodimerization activity; ISS:BHF-UCL. DR GO; GO:0000977; F:RNA polymerase II transcription regulatory region sequence-specific DNA binding; IDA:BHF-UCL. DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; ISS:BHF-UCL. DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; IDA:ARUK-UCL. DR GO; GO:0001223; F:transcription coactivator binding; ISS:BHF-UCL. DR GO; GO:0007512; P:adult heart development; IEP:BHF-UCL. DR GO; GO:0001525; P:angiogenesis; IEA:UniProtKB-KW. DR GO; GO:0003278; P:apoptotic process involved in heart morphogenesis; IEA:Ensembl. DR GO; GO:0061309; P:cardiac neural crest cell development involved in outflow tract morphogenesis; ISS:BHF-UCL. DR GO; GO:0003253; P:cardiac neural crest cell migration involved in outflow tract morphogenesis; IEA:Ensembl. DR GO; GO:0003219; P:cardiac right ventricle formation; IEA:Ensembl. DR GO; GO:0060536; P:cartilage morphogenesis; IEA:Ensembl. DR GO; GO:0061325; P:cell proliferation involved in outflow tract morphogenesis; IEA:Ensembl. DR GO; GO:0071407; P:cellular response to organic cyclic compound; IEA:Ensembl. DR GO; GO:0071300; P:cellular response to retinoic acid; IEA:Ensembl. DR GO; GO:0060982; P:coronary artery morphogenesis; IEA:Ensembl. DR GO; GO:0042733; P:embryonic digit morphogenesis; IEA:Ensembl. DR GO; GO:0048706; P:embryonic skeletal system development; IEA:Ensembl. DR GO; GO:1904019; P:epithelial cell apoptotic process; IEA:Ensembl. DR GO; GO:0007507; P:heart development; IBA:GO_Central. DR GO; GO:0001947; P:heart looping; IEA:Ensembl. DR GO; GO:0001701; P:in utero embryonic development; IEA:Ensembl. DR GO; GO:0010463; P:mesenchymal cell proliferation; IEA:Ensembl. DR GO; GO:0010667; P:negative regulation of cardiac muscle cell apoptotic process; ISS:BHF-UCL. DR GO; GO:1904036; P:negative regulation of epithelial cell apoptotic process; IEA:Ensembl. DR GO; GO:0010629; P:negative regulation of gene expression; IMP:BHF-UCL. DR GO; GO:0045668; P:negative regulation of osteoblast differentiation; IEA:Ensembl. DR GO; GO:0003357; P:noradrenergic neuron differentiation; NAS:BHF-UCL. DR GO; GO:0042421; P:norepinephrine biosynthetic process; IEA:Ensembl. DR GO; GO:0042475; P:odontogenesis of dentin-containing tooth; IEA:Ensembl. DR GO; GO:0001649; P:osteoblast differentiation; IEA:Ensembl. DR GO; GO:0003151; P:outflow tract morphogenesis; ISS:BHF-UCL. DR GO; GO:0048935; P:peripheral nervous system neuron development; IEA:Ensembl. DR GO; GO:0010613; P:positive regulation of cardiac muscle hypertrophy; IDA:BHF-UCL. DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IMP:BHF-UCL. DR GO; GO:0010628; P:positive regulation of gene expression; IMP:BHF-UCL. DR GO; GO:1900745; P:positive regulation of p38MAPK cascade; IMP:BHF-UCL. DR GO; GO:2001262; P:positive regulation of semaphorin-plexin signaling pathway; ISS:BHF-UCL. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:UniProtKB. DR GO; GO:2000679; P:positive regulation of transcription regulatory region DNA binding; IDA:BHF-UCL. DR GO; GO:1903929; P:primary palate development; IEA:Ensembl. DR GO; GO:0003266; P:regulation of secondary heart field cardioblast proliferation; ISS:BHF-UCL. DR GO; GO:0034103; P:regulation of tissue remodeling; IDA:BHF-UCL. DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central. DR GO; GO:0001967; P:suckling behavior; IEA:Ensembl. DR GO; GO:0048485; P:sympathetic nervous system development; IEA:Ensembl. DR GO; GO:0048538; P:thymus development; ISS:BHF-UCL. DR GO; GO:0043586; P:tongue development; IEA:Ensembl. DR GO; GO:0061032; P:visceral serous pericardium development; IEA:Ensembl. DR CDD; cd11471; bHLH_TS_HAND2; 1. DR FunFam; 4.10.280.10:FF:000010; Scleraxis bHLH transcription factor; 1. DR Gene3D; 4.10.280.10; Helix-loop-helix DNA-binding domain; 1. DR InterPro; IPR011598; bHLH_dom. DR InterPro; IPR050283; E-box_TF_Regulators. DR InterPro; IPR036638; HLH_DNA-bd_sf. DR PANTHER; PTHR23349; BASIC HELIX-LOOP-HELIX TRANSCRIPTION FACTOR, TWIST; 1. DR PANTHER; PTHR23349:SF41; HEART- AND NEURAL CREST DERIVATIVES-EXPRESSED PROTEIN 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. PE 1: Evidence at protein level; KW Alternative splicing; Angiogenesis; Developmental protein; Differentiation; KW DNA-binding; Nucleus; Proteomics identification; Reference proteome; KW Transcription; Transcription regulation. FT CHAIN 1..217 FT /note="Heart- and neural crest derivatives-expressed FT protein 2" FT /id="PRO_0000127191" FT DOMAIN 99..151 FT /note="bHLH" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00981" FT REGION 76..116 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 83..94 FT /note="Gly residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 97..112 FT /note="Basic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT VAR_SEQ 21..26 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_056880" FT VAR_SEQ 71..101 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_056881" SQ SEQUENCE 217 AA; 23666 MW; 528F541BB2173F1E CRC64; MSLVGGFPHH PVVHHEGYPF AAAAAAAAAA AASRCSHEEN PYFHGWLIGH PEMSPPDYSM ALSYSPEYAS GAAGLDHSHY GGVPPGAGPP GLGGPRPVKR RGTANRKERR RTQSINSAFA ELRECIPNVP ADTKLSKIKT LRLATSYIAY LMDLLAKDDQ NGEAEAFKAE IKKTDVKEEK RKKELNEILK STVSSNDKKT KGRTGWPQHV WALELKQ //