ID   PRRX1_HUMAN             Reviewed;         245 AA.
AC   P54821; B5BUM7; O60807;
DT   01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT   15-JUL-1999, sequence version 2.
DT   24-JAN-2024, entry version 194.
DE   RecName: Full=Paired mesoderm homeobox protein 1;
DE   AltName: Full=Homeobox protein PHOX1 {ECO:0000303|PubMed:1509260};
DE   AltName: Full=Paired-related homeobox protein 1;
DE            Short=PRX-1;
GN   Name=PRRX1; Synonyms=PMX1;
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] (ISOFORM 1).
RX   PubMed=19054851; DOI=10.1038/nmeth.1273;
RA   Goshima N., Kawamura Y., Fukumoto A., Miura A., Honma R., Satoh R.,
RA   Wakamatsu A., Yamamoto J., Kimura K., Nishikawa T., Andoh T., Iida Y.,
RA   Ishikawa K., Ito E., Kagawa N., Kaminaga C., Kanehori K., Kawakami B.,
RA   Kenmochi K., Kimura R., Kobayashi M., Kuroita T., Kuwayama H., Maruyama Y.,
RA   Matsuo K., Minami K., Mitsubori M., Mori M., Morishita R., Murase A.,
RA   Nishikawa A., Nishikawa S., Okamoto T., Sakagami N., Sakamoto Y.,
RA   Sasaki Y., Seki T., Sono S., Sugiyama A., Sumiya T., Takayama T.,
RA   Takayama Y., Takeda H., Togashi T., Yahata K., Yamada H., Yanagisawa Y.,
RA   Endo Y., Imamoto F., Kisu Y., Tanaka S., Isogai T., Imai J., Watanabe S.,
RA   Nomura N.;
RT   "Human protein factory for converting the transcriptome into an in vitro-
RT   expressed proteome.";
RL   Nat. Methods 5:1011-1017(2008).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=16710414; DOI=10.1038/nature04727;
RA   Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A.,
RA   Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C.,
RA   Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K.,
RA   Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C.,
RA   Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W.,
RA   Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J.,
RA   Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J.,
RA   Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y.,
RA   Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J.,
RA   Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA   Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA   Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA   Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S.,
RA   Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K.,
RA   Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R.,
RA   Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M.,
RA   Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S.,
RA   Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J.,
RA   Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W.,
RA   McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA   Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA   Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA   Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA   Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S.,
RA   Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M.,
RA   White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H.,
RA   Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E.,
RA   Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G.,
RA   Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.;
RT   "The DNA sequence and biological annotation of human chromosome 1.";
RL   Nature 441:315-321(2006).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
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 19-245 (ISOFORM 2).
RX   PubMed=1509260; DOI=10.1126/science.257.5073.1089;
RA   Grueneberg D.A., Natesan S., Alexandre C., Gilman M.Z.;
RT   "Human and Drosophila homeodomain proteins that enhance the DNA-binding
RT   activity of serum response factor.";
RL   Science 257:1089-1095(1992).
RN   [5]
RP   TISSUE SPECIFICITY.
RX   PubMed=11063257; DOI=10.1007/s003350010193;
RA   Norris R.A., Scott K.K., Moore C.S., Stetten G., Brown C.R., Jabs E.W.,
RA   Wulfsberg E.A., Yu J., Kern M.J.;
RT   "Human PRRX1 and PRRX2 genes: cloning, expression, genomic localization,
RT   and exclusion as disease genes for Nager syndrome.";
RL   Mamm. Genome 11:1000-1005(2000).
RN   [6]
RP   VARIANT AGOTC SER-113.
RX   PubMed=21294718; DOI=10.1111/j.1399-0004.2010.01531.x;
RA   Sergi C., Kamnasaran D.;
RT   "PRRX1 is mutated in a fetus with agnathia-otocephaly.";
RL   Clin. Genet. 79:293-295(2011).
RN   [7]
RP   FUNCTION, AND DISEASE.
RX   PubMed=35589735; DOI=10.1038/s41467-022-30484-4;
RA   Lee K.W., Yeo S.Y., Gong J.R., Koo O.J., Sohn I., Lee W.Y., Kim H.C.,
RA   Yun S.H., Cho Y.B., Choi M.A., An S., Kim J., Sung C.O., Cho K.H.,
RA   Kim S.H.;
RT   "PRRX1 is a master transcription factor of stromal fibroblasts for
RT   myofibroblastic lineage progression.";
RL   Nat. Commun. 13:2793-2793(2022).
CC   -!- FUNCTION: Master transcription factor of stromal fibroblasts for
CC       myofibroblastic lineage progression. Orchestrates the functional drift
CC       of fibroblasts into myofibroblastic phenotype via TGF-beta signaling by
CC       remodeling a super-enhancer landscape. Through this function, plays an
CC       essential role in wound healing process (PubMed:35589735). Acts as a
CC       transcriptional regulator of muscle creatine kinase (MCK) and so has a
CC       role in the establishment of diverse mesodermal muscle types. The
CC       protein binds to an A/T-rich element in the muscle creatine enhancer
CC       (By similarity). May play a role in homeostasis and regeneration of
CC       bone, white adipose tissue and derm (By similarity).
CC       {ECO:0000250|UniProtKB:P63013, ECO:0000269|PubMed:35589735}.
CC   -!- FUNCTION: [Isoform 1]: Transcriptional activator, when transfected in
CC       fibroblastic or myoblastic cell lines. This activity may be masked by
CC       the C-terminal OAR domain. {ECO:0000250|UniProtKB:P63013}.
CC   -!- FUNCTION: [Isoform 2]: Transcriptional repressor, when transfected in
CC       fibroblastic or myoblastic cell lines. {ECO:0000250|UniProtKB:P63013}.
CC   -!- SUBUNIT: Interacts with SMAD3. {ECO:0000250|UniProtKB:P63013}.
CC   -!- INTERACTION:
CC       P54821; Q9BW66: CINP; NbExp=3; IntAct=EBI-12828023, EBI-739784;
CC       P54821; P51687: SUOX; NbExp=3; IntAct=EBI-12828023, EBI-3921347;
CC   -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:P63013}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1; Synonyms=PRRX1a {ECO:0000303|PubMed:11063257}, PMX1-B
CC       {ECO:0000303|PubMed:19054851};
CC         IsoId=P54821-1; Sequence=Displayed;
CC       Name=2; Synonyms=PRRX1b {ECO:0000303|PubMed:11063257};
CC         IsoId=P54821-2; Sequence=VSP_002278;
CC   -!- TISSUE SPECIFICITY: [Isoform 1]: Widely expressed in embryonic and
CC       adult tissues, with highest levels in skeletal muscle. Isoform 1 is
CC       either expressed at similar or higher levels compared to isoform 2 in
CC       all embryonic tissues but skeletal muscle and heart. In adult tissues,
CC       expressed at lower levels compared to isoform 2.
CC       {ECO:0000269|PubMed:11063257}.
CC   -!- TISSUE SPECIFICITY: [Isoform 2]: Widely expressed in embryonic and
CC       adult tissues, with highest levels in skeletal muscle. Isoform 2 is
CC       either expressed at similar or lower levels compared to isoform 1 in
CC       all embryonic tissues but skeletal muscle and heart, where it is
CC       expressed at higher levels. In adult tissues, expressed at higher
CC       levels compared to isoform 1. {ECO:0000269|PubMed:11063257}.
CC   -!- DISEASE: Agnathia-otocephaly complex (AGOTC) [MIM:202650]: A rare
CC       condition characterized by mandibular hypoplasia or agnathia,
CC       ventromedial auricular malposition (melotia) and/or auricular fusion
CC       (synotia), and microstomia with oroglossal hypoplasia or aglossia.
CC       Holoprosencephaly is the most commonly identified association, but
CC       skeletal, genitourinary, and cardiovascular anomalies, and situs
CC       inversus have been reported. The disorder is almost always lethal.
CC       {ECO:0000269|PubMed:21294718}. Note=The disease is caused by variants
CC       affecting the gene represented in this entry.
CC   -!- DISEASE: Note=Strongly expressed in cancer-associated fibroblasts
CC       (CAFs) in various cancer types. Its expression correlates with
CC       unfavorable clinical outcome. May be essential for the tumorigenicity
CC       and metastasis-inducing capacity of CAFs. Can reprogram tumor-
CC       suppressive normal fibroblasts into CAFs.
CC       {ECO:0000269|PubMed:35589735}.
CC   -!- SIMILARITY: Belongs to the paired homeobox family. {ECO:0000305}.
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DR   EMBL; AB451463; BAG70277.1; -; mRNA.
DR   EMBL; Z97200; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC074993; AAH74993.1; -; mRNA.
DR   EMBL; M95929; AAA60085.1; -; mRNA.
DR   CCDS; CCDS1290.1; -. [P54821-1]
DR   CCDS; CCDS1291.1; -. [P54821-2]
DR   RefSeq; NP_008833.1; NM_006902.4. [P54821-2]
DR   RefSeq; NP_073207.1; NM_022716.3. [P54821-1]
DR   AlphaFoldDB; P54821; -.
DR   SMR; P54821; -.
DR   BioGRID; 111405; 10.
DR   CORUM; P54821; -.
DR   IntAct; P54821; 2.
DR   STRING; 9606.ENSP00000239461; -.
DR   ChEMBL; CHEMBL4879442; -.
DR   GlyGen; P54821; 1 site, 1 O-linked glycan (1 site).
DR   iPTMnet; P54821; -.
DR   PhosphoSitePlus; P54821; -.
DR   BioMuta; PRRX1; -.
DR   DMDM; 6174916; -.
DR   jPOST; P54821; -.
DR   MassIVE; P54821; -.
DR   PaxDb; 9606-ENSP00000239461; -.
DR   PeptideAtlas; P54821; -.
DR   ProteomicsDB; 56732; -. [P54821-1]
DR   ProteomicsDB; 56733; -. [P54821-2]
DR   Antibodypedia; 34372; 498 antibodies from 31 providers.
DR   DNASU; 5396; -.
DR   Ensembl; ENST00000239461.11; ENSP00000239461.6; ENSG00000116132.12. [P54821-1]
DR   Ensembl; ENST00000367760.7; ENSP00000356734.3; ENSG00000116132.12. [P54821-2]
DR   GeneID; 5396; -.
DR   KEGG; hsa:5396; -.
DR   MANE-Select; ENST00000239461.11; ENSP00000239461.6; NM_022716.4; NP_073207.1.
DR   UCSC; uc001ghe.4; human. [P54821-1]
DR   AGR; HGNC:9142; -.
DR   CTD; 5396; -.
DR   DisGeNET; 5396; -.
DR   GeneCards; PRRX1; -.
DR   HGNC; HGNC:9142; PRRX1.
DR   HPA; ENSG00000116132; Low tissue specificity.
DR   MalaCards; PRRX1; -.
DR   MIM; 167420; gene.
DR   MIM; 202650; phenotype.
DR   neXtProt; NX_P54821; -.
DR   OpenTargets; ENSG00000116132; -.
DR   Orphanet; 990; Agnathia-holoprosencephaly-situs inversus syndrome.
DR   PharmGKB; PA33466; -.
DR   VEuPathDB; HostDB:ENSG00000116132; -.
DR   eggNOG; KOG0490; Eukaryota.
DR   GeneTree; ENSGT00940000159466; -.
DR   InParanoid; P54821; -.
DR   OMA; YAHAMDR; -.
DR   OrthoDB; 3685623at2759; -.
DR   PhylomeDB; P54821; -.
DR   TreeFam; TF351612; -.
DR   PathwayCommons; P54821; -.
DR   SignaLink; P54821; -.
DR   SIGNOR; P54821; -.
DR   BioGRID-ORCS; 5396; 12 hits in 1170 CRISPR screens.
DR   ChiTaRS; PRRX1; human.
DR   GeneWiki; PRRX1; -.
DR   GenomeRNAi; 5396; -.
DR   Pharos; P54821; Tbio.
DR   PRO; PR:P54821; -.
DR   Proteomes; UP000005640; Chromosome 1.
DR   RNAct; P54821; Protein.
DR   Bgee; ENSG00000116132; Expressed in calcaneal tendon and 189 other cell types or tissues.
DR   ExpressionAtlas; P54821; baseline and differential.
DR   GO; GO:0000785; C:chromatin; ISA:NTNU_SB.
DR   GO; GO:0005829; C:cytosol; IDA:HPA.
DR   GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR   GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR   GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IDA:ARUK-UCL.
DR   GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISA:NTNU_SB.
DR   GO; GO:0001227; F:DNA-binding transcription repressor activity, RNA polymerase II-specific; IEA:Ensembl.
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; IDA:GO_Central.
DR   GO; GO:0016251; F:RNA polymerase II general transcription initiation factor activity; IEA:Ensembl.
DR   GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; IPI:ARUK-UCL.
DR   GO; GO:0048844; P:artery morphogenesis; IEA:Ensembl.
DR   GO; GO:0051216; P:cartilage development; IEA:Ensembl.
DR   GO; GO:0048701; P:embryonic cranial skeleton morphogenesis; IEA:Ensembl.
DR   GO; GO:0030326; P:embryonic limb morphogenesis; IEA:Ensembl.
DR   GO; GO:0042472; P:inner ear morphogenesis; IEA:Ensembl.
DR   GO; GO:0010463; P:mesenchymal cell proliferation; IEA:Ensembl.
DR   GO; GO:0042474; P:middle ear morphogenesis; IEA:Ensembl.
DR   GO; GO:0048664; P:neuron fate determination; IEA:Ensembl.
DR   GO; GO:0097150; P:neuronal stem cell population maintenance; IEA:Ensembl.
DR   GO; GO:0002053; P:positive regulation of mesenchymal cell proliferation; IEA:Ensembl.
DR   GO; GO:0045880; P:positive regulation of smoothened signaling pathway; IEA:Ensembl.
DR   GO; GO:2000648; P:positive regulation of stem cell proliferation; IEA:Ensembl.
DR   GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:ARUK-UCL.
DR   GO; GO:0070570; P:regulation of neuron projection regeneration; IEA:Ensembl.
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:0007224; P:smoothened signaling pathway; IEA:Ensembl.
DR   GO; GO:0072089; P:stem cell proliferation; IEA:Ensembl.
DR   CDD; cd00086; homeodomain; 1.
DR   Gene3D; 1.10.10.60; Homeodomain-like; 1.
DR   InterPro; IPR009057; Homeobox-like_sf.
DR   InterPro; IPR017970; Homeobox_CS.
DR   InterPro; IPR001356; Homeobox_dom.
DR   InterPro; IPR003654; OAR_dom.
DR   InterPro; IPR043378; PRRX1/2.
DR   PANTHER; PTHR46385:SF1; PAIRED MESODERM HOMEOBOX PROTEIN 1; 1.
DR   PANTHER; PTHR46385; PAIRED MESODERM HOMEOBOX PROTEIN 1-RELATED; 1.
DR   Pfam; PF00046; Homeodomain; 1.
DR   Pfam; PF03826; OAR; 1.
DR   SMART; SM00389; HOX; 1.
DR   SUPFAM; SSF46689; Homeodomain-like; 1.
DR   PROSITE; PS00027; HOMEOBOX_1; 1.
DR   PROSITE; PS50071; HOMEOBOX_2; 1.
DR   PROSITE; PS50803; OAR; 1.
DR   Genevisible; P54821; HS.
PE   1: Evidence at protein level;
KW   Acetylation; Alternative splicing; Developmental protein; Disease variant;
KW   DNA-binding; Homeobox; Nucleus; Phosphoprotein; Reference proteome.
FT   CHAIN           1..245
FT                   /note="Paired mesoderm homeobox protein 1"
FT                   /id="PRO_0000049251"
FT   DNA_BIND        94..153
FT                   /note="Homeobox"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00108"
FT   REGION          1..22
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          63..103
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOTIF           222..235
FT                   /note="OAR"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00138"
FT   COMPBIAS        67..81
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOD_RES         21
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P63014"
FT   MOD_RES         160
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P63013"
FT   MOD_RES         197
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000255"
FT   VAR_SEQ         200..245
FT                   /note="SAMATYSATCANNSPAQGINMANSIANLRLKAKEYSLQRNQVPTVN -> RS
FT                   SSLPRCCLHEGLHNGF (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:1509260"
FT                   /id="VSP_002278"
FT   VARIANT         113
FT                   /note="F -> S (in AGOTC; dbSNP:rs387906667)"
FT                   /evidence="ECO:0000269|PubMed:21294718"
FT                   /id="VAR_066414"
SQ   SEQUENCE   245 AA;  27296 MW;  7CA4B7FD9492FC19 CRC64;
     MTSSYGHVLE RQPALGGRLD SPGNLDTLQA KKNFSVSHLL DLEEAGDMVA AQADENVGEA
     GRSLLESPGL TSGSDTPQQD NDQLNSEEKK KRKQRRNRTT FNSSQLQALE RVFERTHYPD
     AFVREDLARR VNLTEARVQV WFQNRRAKFR RNERAMLANK NASLLKSYSG DVTAVEQPIV
     PRPAPRPTDY LSWGTASPYS AMATYSATCA NNSPAQGINM ANSIANLRLK AKEYSLQRNQ
     VPTVN
//