DLX5_HUMAN
ID DLX5_HUMAN Reviewed; 289 AA.
AC P56178; B7Z4P3; Q9UPL1;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 11-JAN-2001, sequence version 2.
DT 03-AUG-2022, entry version 191.
DE RecName: Full=Homeobox protein DLX-5;
GN Name=DLX5;
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 [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Brain, and Placenta;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12853948; DOI=10.1038/nature01782;
RA Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H.,
RA Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., Wylie K.,
RA Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., Fewell G.A.,
RA Delehaunty K.D., Miner T.L., Nash W.E., Cordes M., Du H., Sun H.,
RA Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., Vanbrunt A.,
RA Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., Ozersky P.,
RA Bielicki L., Scott K., Holmes A., Harkins R., Harris A., Strong C.M.,
RA Hou S., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Leonard S.,
RA Rohlfing T., Rock S.M., Tin-Wollam A.-M., Abbott A., Minx P., Maupin R.,
RA Strowmatt C., Latreille P., Miller N., Johnson D., Murray J.,
RA Woessner J.P., Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W.,
RA Spieth J., Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Bedell J.A.,
RA Mardis E.R., Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E.,
RA Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K., Simms E.,
RA Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., Baertsch R.A.,
RA Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., Bailey J.A.,
RA Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., Eddy S.R.,
RA McPherson J.D., Olson M.V., Eichler E.E., Green E.D., Waterston R.H.,
RA Wilson R.K.;
RT "The DNA sequence of human chromosome 7.";
RL Nature 424:157-164(2003).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Lung;
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 NUCLEOTIDE SEQUENCE [MRNA] OF 137-202 (ISOFORM 1).
RC TISSUE=Embryo;
RX PubMed=7907794; DOI=10.1073/pnas.91.6.2250;
RA Simeone A., Acampora D., Pannese M., D'Esposito M., Stornaiuolo A.,
RA Gulisano M., Mallamaci A., Kastury K., Druck T., Huebner K., Boncinelli E.;
RT "Cloning and characterization of two members of the vertebrate Dlx gene
RT family.";
RL Proc. Natl. Acad. Sci. U.S.A. 91:2250-2254(1994).
RN [5]
RP INTERACTION WITH XRCC6.
RC TISSUE=Osteoblast;
RX PubMed=12145306; DOI=10.1074/jbc.m206482200;
RA Willis D.M., Loewy A.P., Charlton-Kachigian N., Shao J.-S., Ornitz D.M.,
RA Towler D.A.;
RT "Regulation of osteocalcin gene expression by a novel Ku antigen
RT transcription factor complex.";
RL J. Biol. Chem. 277:37280-37291(2002).
RN [6]
RP FUNCTION, AND DNA-BINDING.
RX PubMed=19497851; DOI=10.1074/jbc.m109.021477;
RA Xu J., Testa J.R.;
RT "DLX5 (distal-less homeobox 5) promotes tumor cell proliferation by
RT transcriptionally regulating MYC.";
RL J. Biol. Chem. 284:20593-20601(2009).
RN [7]
RP STRUCTURE BY NMR OF 138-194.
RG RIKEN structural genomics initiative (RSGI);
RT "The solution structure of the homeobox domain of human homeobox protein
RT DLX-5.";
RL Submitted (OCT-2006) to the PDB data bank.
RN [8]
RP VARIANT SHFM1D PRO-178.
RX PubMed=22121204; DOI=10.1136/jmedgenet-2011-100556;
RA Shamseldin H.E., Faden M.A., Alashram W., Alkuraya F.S.;
RT "Identification of a novel DLX5 mutation in a family with autosomal
RT recessive split hand and foot malformation.";
RL J. Med. Genet. 49:16-20(2012).
CC -!- FUNCTION: Transcriptional factor involved in bone development. Acts as
CC an immediate early BMP-responsive transcriptional activator essential
CC for osteoblast differentiation. Stimulates ALPL promoter activity in a
CC RUNX2-independent manner during osteoblast differentiation. Stimulates
CC SP7 promoter activity during osteoblast differentiation. Promotes cell
CC proliferation by up-regulating MYC promoter activity. Involved as a
CC positive regulator of both chondrogenesis and chondrocyte hypertrophy
CC in the endochondral skeleton. Binds to the homeodomain-response element
CC of the ALPL and SP7 promoter. Binds to the MYC promoter. Requires the
CC 5'-TAATTA-3' consensus sequence for DNA-binding.
CC {ECO:0000269|PubMed:19497851}.
CC -!- SUBUNIT: Interacts with XRCC6 (Ku70). {ECO:0000269|PubMed:12145306}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000255|PROSITE-ProRule:PRU00108}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P56178-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P56178-2; Sequence=VSP_056884;
CC -!- DEVELOPMENTAL STAGE: First expressed in embryos at 8.5-9 days in facial
CC and branchial arch mesenchyme, otic vesicles and frontonasal ectoderm
CC around olfactory placodes, a day later expression is seen in the
CC developing forebrain in primordia of the ganglionic eminence and
CC ventral diencephalic regions. In day 12.5 embryos, expressed in the
CC brain and bones, and also in all skeletal structures of midgestation
CC embryos after the first cartilage formation. Expression remains
CC unaltered in both brain and skeleton in day 15 embryos and slowly
CC decreases in day 17 embryos.
CC -!- PTM: Phosphorylated. Phosphorylation of Ser-34 and Ser-217 by MAPK14
CC enhances its transcriptional activity. Phosphorylation by CaMK2
CC increases its protein stability (By similarity). {ECO:0000250}.
CC -!- DISEASE: Split-hand/foot malformation 1 with sensorineural hearing
CC loss, autosomal recessive (SHFM1D) [MIM:220600]: A disease
CC characterized by the association of split-hand/foot malformation with
CC deafness. Split-hand/foot malformation is a limb malformation involving
CC the central rays of the autopod and presenting with syndactyly, median
CC clefts of the hands and feet, and aplasia and/or hypoplasia of the
CC phalanges, metacarpals, and metatarsals. Some patients have been found
CC to have intellectual disability, ectodermal and craniofacial findings,
CC and orofacial clefting. {ECO:0000269|PubMed:22121204}. Note=The disease
CC is caused by variants affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the distal-less homeobox family. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/DLX5ID44295ch7q21.html";
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DR EMBL; AK023493; BAB14587.1; -; mRNA.
DR EMBL; AK297614; BAH12629.1; -; mRNA.
DR EMBL; AC004774; AAC17833.1; -; Genomic_DNA.
DR EMBL; BC006226; AAH06226.1; -; mRNA.
DR CCDS; CCDS5647.1; -. [P56178-1]
DR PIR; C53495; C53495.
DR RefSeq; NP_005212.1; NM_005221.5. [P56178-1]
DR PDB; 2DJN; NMR; -; A=138-194.
DR PDB; 4RDU; X-ray; 1.85 A; A/D=135-198.
DR PDBsum; 2DJN; -.
DR PDBsum; 4RDU; -.
DR AlphaFoldDB; P56178; -.
DR BMRB; P56178; -.
DR SMR; P56178; -.
DR BioGRID; 108093; 15.
DR IntAct; P56178; 9.
DR MINT; P56178; -.
DR STRING; 9606.ENSP00000222598; -.
DR iPTMnet; P56178; -.
DR PhosphoSitePlus; P56178; -.
DR BioMuta; DLX5; -.
DR DMDM; 12644329; -.
DR MassIVE; P56178; -.
DR PaxDb; P56178; -.
DR PeptideAtlas; P56178; -.
DR PRIDE; P56178; -.
DR ProteomicsDB; 56892; -. [P56178-1]
DR Antibodypedia; 1428; 520 antibodies from 40 providers.
DR DNASU; 1749; -.
DR Ensembl; ENST00000486603.2; ENSP00000475008.1; ENSG00000105880.7. [P56178-2]
DR Ensembl; ENST00000648378.1; ENSP00000498116.1; ENSG00000105880.7. [P56178-1]
DR GeneID; 1749; -.
DR KEGG; hsa:1749; -.
DR MANE-Select; ENST00000648378.1; ENSP00000498116.1; NM_005221.6; NP_005212.1.
DR UCSC; uc011kim.2; human. [P56178-1]
DR CTD; 1749; -.
DR DisGeNET; 1749; -.
DR GeneCards; DLX5; -.
DR HGNC; HGNC:2918; DLX5.
DR HPA; ENSG00000105880; Tissue enhanced (endometrium, placenta, skin).
DR MalaCards; DLX5; -.
DR MIM; 220600; phenotype.
DR MIM; 600028; gene.
DR neXtProt; NX_P56178; -.
DR OpenTargets; ENSG00000105880; -.
DR Orphanet; 2440; Isolated split hand-split foot malformation.
DR Orphanet; 71271; Split hand-split foot-deafness syndrome.
DR PharmGKB; PA27373; -.
DR VEuPathDB; HostDB:ENSG00000105880; -.
DR eggNOG; KOG0850; Eukaryota.
DR GeneTree; ENSGT00940000159188; -.
DR HOGENOM; CLU_074733_0_0_1; -.
DR InParanoid; P56178; -.
DR OMA; THGYCSP; -.
DR PhylomeDB; P56178; -.
DR TreeFam; TF350606; -.
DR PathwayCommons; P56178; -.
DR Reactome; R-HSA-8939902; Regulation of RUNX2 expression and activity.
DR SignaLink; P56178; -.
DR SIGNOR; P56178; -.
DR BioGRID-ORCS; 1749; 10 hits in 1093 CRISPR screens.
DR EvolutionaryTrace; P56178; -.
DR GeneWiki; DLX5; -.
DR GenomeRNAi; 1749; -.
DR Pharos; P56178; Tbio.
DR PRO; PR:P56178; -.
DR Proteomes; UP000005640; Chromosome 7.
DR RNAct; P56178; protein.
DR Bgee; ENSG00000105880; Expressed in tibia and 100 other tissues.
DR ExpressionAtlas; P56178; baseline and differential.
DR Genevisible; P56178; HS.
DR GO; GO:0000785; C:chromatin; ISS:BHF-UCL.
DR GO; GO:0005737; C:cytoplasm; IEA:Ensembl.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; ISS:BHF-UCL.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISA:NTNU_SB.
DR GO; GO:0071837; F:HMG box domain binding; IEA:Ensembl.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; ISS:BHF-UCL.
DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; IDA:ARUK-UCL.
DR GO; GO:0000976; F:transcription cis-regulatory region binding; IDA:UniProtKB.
DR GO; GO:0048646; P:anatomical structure formation involved in morphogenesis; IBA:GO_Central.
DR GO; GO:0030509; P:BMP signaling pathway; ISS:BHF-UCL.
DR GO; GO:0030154; P:cell differentiation; IBA:GO_Central.
DR GO; GO:0008283; P:cell population proliferation; IDA:UniProtKB.
DR GO; GO:0071773; P:cellular response to BMP stimulus; ISS:BHF-UCL.
DR GO; GO:0030326; P:embryonic limb morphogenesis; IEA:Ensembl.
DR GO; GO:0001958; P:endochondral ossification; ISS:UniProtKB.
DR GO; GO:0030855; P:epithelial cell differentiation; IEA:Ensembl.
DR GO; GO:0060325; P:face morphogenesis; IEA:Ensembl.
DR GO; GO:0042472; P:inner ear morphogenesis; IEA:Ensembl.
DR GO; GO:0097376; P:interneuron axon guidance; IEA:Ensembl.
DR GO; GO:0007399; P:nervous system development; TAS:ProtInc.
DR GO; GO:0021889; P:olfactory bulb interneuron differentiation; IEA:Ensembl.
DR GO; GO:0060166; P:olfactory pit development; IEA:Ensembl.
DR GO; GO:0001649; P:osteoblast differentiation; ISS:UniProtKB.
DR GO; GO:0090263; P:positive regulation of canonical Wnt signaling pathway; IEA:Ensembl.
DR GO; GO:0050679; P:positive regulation of epithelial cell proliferation; IEA:Ensembl.
DR GO; GO:0010628; P:positive regulation of gene expression; IEA:Ensembl.
DR GO; GO:1901522; P:positive regulation of transcription from RNA polymerase II promoter involved in cellular response to chemical stimulus; ISS:BHF-UCL.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IDA:UniProtKB.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0060021; P:roof of mouth development; IEA:Ensembl.
DR GO; GO:0001501; P:skeletal system development; TAS:ProtInc.
DR CDD; cd00086; homeodomain; 1.
DR InterPro; IPR022135; Distal-less_N.
DR InterPro; IPR009057; Homeobox-like_sf.
DR InterPro; IPR017970; Homeobox_CS.
DR InterPro; IPR001356; Homeobox_dom.
DR InterPro; IPR020479; Homeobox_metazoa.
DR InterPro; IPR000047; HTH_motif.
DR Pfam; PF12413; DLL_N; 1.
DR Pfam; PF00046; Homeodomain; 1.
DR PRINTS; PR00024; HOMEOBOX.
DR PRINTS; PR00031; HTHREPRESSR.
DR SMART; SM00389; HOX; 1.
DR SUPFAM; SSF46689; SSF46689; 1.
DR PROSITE; PS00027; HOMEOBOX_1; 1.
DR PROSITE; PS50071; HOMEOBOX_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Activator; Alternative splicing; Deafness;
KW Developmental protein; Disease variant; DNA-binding; Homeobox; Nucleus;
KW Osteogenesis; Phosphoprotein; Reference proteome; Transcription;
KW Transcription regulation.
FT CHAIN 1..289
FT /note="Homeobox protein DLX-5"
FT /id="PRO_0000049031"
FT DNA_BIND 137..196
FT /note="Homeobox"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00108"
FT REGION 1..49
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 198..251
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 270..289
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 16..48
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 203..251
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 34
FT /note="Phosphoserine; by MAPK14; in vitro"
FT /evidence="ECO:0000250|UniProtKB:P70396"
FT MOD_RES 217
FT /note="Phosphoserine; by MAPK14; in vitro"
FT /evidence="ECO:0000250|UniProtKB:P70396"
FT VAR_SEQ 182..289
FT /note="KIWFQNKRSKIKKIMKNGEMPPEHSPSSSDPMACNSPQSPAVWEPQGSSRSL
FT SHHPHAHPPTSNQSPASSYLENSASWYTSAASSINSHLPPPGSLQHPLALASGTLY ->
FT NTALPCTRPA (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_056884"
FT VARIANT 178
FT /note="Q -> P (in SHFM1D; dbSNP:rs387906737)"
FT /evidence="ECO:0000269|PubMed:22121204"
FT /id="VAR_067413"
FT VARIANT 234
FT /note="S -> R (in dbSNP:rs35273378)"
FT /id="VAR_033874"
FT HELIX 146..158
FT /evidence="ECO:0007829|PDB:4RDU"
FT HELIX 164..173
FT /evidence="ECO:0007829|PDB:4RDU"
FT HELIX 178..196
FT /evidence="ECO:0007829|PDB:4RDU"
SQ SEQUENCE 289 AA; 31540 MW; 5BC9970B12E30554 CRC64;
MTGVFDRRVP SIRSGDFQAP FQTSAAMHHP SQESPTLPES SATDSDYYSP TGGAPHGYCS
PTSASYGKAL NPYQYQYHGV NGSAGSYPAK AYADYSYASS YHQYGGAYNR VPSATNQPEK
EVTEPEVRMV NGKPKKVRKP RTIYSSFQLA ALQRRFQKTQ YLALPERAEL AASLGLTQTQ
VKIWFQNKRS KIKKIMKNGE MPPEHSPSSS DPMACNSPQS PAVWEPQGSS RSLSHHPHAH
PPTSNQSPAS SYLENSASWY TSAASSINSH LPPPGSLQHP LALASGTLY
