PMEPA_HUMAN
ID PMEPA_HUMAN Reviewed; 287 AA.
AC Q969W9; Q5TDR6; Q8NER4; Q96B72; Q9UJD3;
DT 05-MAR-2002, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-2001, sequence version 1.
DT 03-AUG-2022, entry version 156.
DE RecName: Full=Protein TMEPAI;
DE AltName: Full=Prostate transmembrane protein androgen induced 1;
DE AltName: Full=Solid tumor-associated 1 protein;
DE AltName: Full=Transmembrane prostate androgen-induced protein;
GN Name=PMEPA1; Synonyms=STAG1, TMEPAI;
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] (ISOFORM 2).
RX PubMed=10873380; DOI=10.1006/geno.2000.6214;
RA Xu L.L., Shanmugam N., Segawa T., Sesterhenn I.A., McLeod D.G., Moul J.W.,
RA Srivastava S.;
RT "A novel androgen-regulated gene, PMEPA1, located on chromosome 20q13
RT exhibits high level expression in prostate.";
RL Genomics 66:257-263(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=11568975; DOI=10.1002/mc.1063;
RA Rae F.K., Hooper J.D., Nicol D.L., Clements J.A.;
RT "Characterization of a novel gene, STAG1/PMEPA1, upregulated in renal cell
RT carcinoma and other solid tumors.";
RL Mol. Carcinog. 32:44-53(2001).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RX PubMed=12670906;
RA Brunschwig E.B., Wilson K., Mack D., Dawson D., Lawrence E.,
RA Willson J.K.V., Lu S., Nosrati A., Rerko R.M., Swinler S., Beard L.,
RA Lutterbaugh J.D., Willis J., Platzer P., Markowitz S.;
RT "PMEPA1, a transforming growth factor-beta-induced marker of terminal
RT colonocyte differentiation whose expression is maintained in primary and
RT metastatic colon cancer.";
RL Cancer Res. 63:1568-1575(2003).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=11780052; DOI=10.1038/414865a;
RA Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R.,
RA Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L.,
RA Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M., Beasley O.P.,
RA Bird C.P., Blakey S.E., Bridgeman A.M., Brown A.J., Buck D., Burrill W.D.,
RA Butler A.P., Carder C., Carter N.P., Chapman J.C., Clamp M., Clark G.,
RA Clark L.N., Clark S.Y., Clee C.M., Clegg S., Cobley V.E., Collier R.E.,
RA Connor R.E., Corby N.R., Coulson A., Coville G.J., Deadman R., Dhami P.D.,
RA Dunn M., Ellington A.G., Frankland J.A., Fraser A., French L., Garner P.,
RA Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E.,
RA Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J.,
RA Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D.,
RA Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S.,
RA Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D.,
RA Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A.,
RA Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T.,
RA Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I.,
RA Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H., Rice C.M.,
RA Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., Skuce C.D.,
RA Smith M.L., Soderlund C., Steward C.A., Sulston J.E., Swann R.M.,
RA Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., Tracey A.,
RA Tromans A.C., Vaudin M., Wall M., Wallis J.M., Whitehead S.L.,
RA Whittaker P., Willey D.L., Williams L., Williams S.A., Wilming L.,
RA Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 20.";
RL Nature 414:865-871(2001).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 8-287 (ISOFORM 1).
RC TISSUE=Kidney;
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 [7]
RP INTERACTION WITH NEDD4, AND MUTAGENESIS OF TYR-161 AND TYR-232.
RX PubMed=12907594;
RA Xu L.L., Shi Y., Petrovics G., Sun C., Makarem M., Zhang W.,
RA Sesterhenn I.A., McLeod D.G., Sun L., Moul J.W., Srivastava S.;
RT "PMEPA1, an androgen-regulated NEDD4-binding protein, exhibits cell growth
RT inhibitory function and decreased expression during prostate cancer
RT progression.";
RL Cancer Res. 63:4299-4304(2003).
RN [8]
RP FUNCTION, INTERACTION WITH AR, MOTIFS, MUTAGENESIS OF TYR-161 AND TYR-232,
RP AND INDUCTION BY ANDROGEN.
RX PubMed=18703514; DOI=10.1074/jbc.m710528200;
RA Li H., Xu L.L., Masuda K., Raymundo E., McLeod D.G., Dobi A.,
RA Srivastava S.;
RT "A feedback loop between the androgen receptor and a NEDD4-binding protein,
RT PMEPA1, in prostate cancer cells.";
RL J. Biol. Chem. 283:28988-28995(2008).
RN [9]
RP FUNCTION, INTERACTION WITH SMAD2 AND SMAD3, SUBCELLULAR LOCATION, MOTIF,
RP AND INDUCTION BY TGF-BETA.
RX PubMed=20129061; DOI=10.1016/j.molcel.2009.10.028;
RA Watanabe Y., Itoh S., Goto T., Ohnishi E., Inamitsu M., Itoh F., Satoh K.,
RA Wiercinska E., Yang W., Shi L., Tanaka A., Nakano N., Mommaas A.M.,
RA Shibuya H., Ten Dijke P., Kato M.;
RT "TMEPAI, a transmembrane TGF-beta-inducible protein, sequesters Smad
RT proteins from active participation in TGF-beta signaling.";
RL Mol. Cell 37:123-134(2010).
RN [10]
RP FUNCTION, INTERACTION WITH LDLRAD4, AND SUBCELLULAR LOCATION.
RX PubMed=24627487; DOI=10.1074/jbc.m114.558981;
RA Nakano N., Maeyama K., Sakata N., Itoh F., Akatsu R., Nakata M., Katsu Y.,
RA Ikeno S., Togawa Y., Vo Nguyen T.T., Watanabe Y., Kato M., Itoh S.;
RT "C18 ORF1, a novel negative regulator of transforming growth factor-beta
RT signaling.";
RL J. Biol. Chem. 289:12680-12692(2014).
CC -!- FUNCTION: Functions as a negative regulator of TGF-beta signaling and
CC thereby probably plays a role in cell proliferation, differentiation,
CC apoptosis, motility, extracellular matrix production and
CC immunosuppression. In the canonical TGF-beta pathway, ZFYVE9/SARA
CC recruits the intracellular signal transducer and transcriptional
CC modulators SMAD2 and SMAD3 to the TGF-beta receptor. Phosphorylated by
CC the receptor, SMAD2 and SMAD3 then form a heteromeric complex with
CC SMAD4 that translocates to the nucleus to regulate transcription.
CC Through interaction with SMAD2 and SMAD3, LDLRAD4 may compete with
CC ZFYVE9 and SMAD4 and prevent propagation of the intracellular signal
CC (PubMed:20129061, PubMed:24627487). Also involved in down-regulation of
CC the androgen receptor (AR), enhancing ubiquitination and proteasome-
CC mediated degradation of AR, probably by recruiting NEDD4
CC (PubMed:18703514). {ECO:0000269|PubMed:18703514,
CC ECO:0000269|PubMed:20129061, ECO:0000269|PubMed:24627487}.
CC -!- SUBUNIT: Interacts with NEDD4 (via PPxY motifs). Interacts with AR.
CC Interacts with LDLRAD4. Interacts (via the SMAD interaction motif) with
CC SMAD2 and SMAD3. {ECO:0000269|PubMed:12907594,
CC ECO:0000269|PubMed:18703514, ECO:0000269|PubMed:20129061,
CC ECO:0000269|PubMed:24627487}.
CC -!- INTERACTION:
CC Q969W9-2; O95208-2: EPN2; NbExp=3; IntAct=EBI-13318883, EBI-12135243;
CC Q969W9-2; Q96DC9: OTUB2; NbExp=3; IntAct=EBI-13318883, EBI-746259;
CC Q969W9-2; O43765: SGTA; NbExp=3; IntAct=EBI-13318883, EBI-347996;
CC Q969W9-2; P57075-2: UBASH3A; NbExp=3; IntAct=EBI-13318883, EBI-7353612;
CC Q969W9-2; Q9UHD9: UBQLN2; NbExp=3; IntAct=EBI-13318883, EBI-947187;
CC -!- SUBCELLULAR LOCATION: Early endosome membrane; Single-pass membrane
CC protein. Golgi apparatus membrane; Single-pass membrane protein.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1; Synonyms=a;
CC IsoId=Q969W9-1; Sequence=Displayed;
CC Name=2; Synonyms=b;
CC IsoId=Q969W9-2; Sequence=VSP_006438;
CC Name=3; Synonyms=c;
CC IsoId=Q969W9-3; Sequence=VSP_044588;
CC -!- TISSUE SPECIFICITY: Highest expression in prostate. Also expressed in
CC ovary.
CC -!- INDUCTION: Up-regulated by androgen and TGF-beta (at protein level).
CC {ECO:0000269|PubMed:18703514, ECO:0000269|PubMed:20129061}.
CC -!- DOMAIN: The PPxY motifs mediate interaction with NEDD4.
CC {ECO:0000269|PubMed:18703514}.
CC -!- DOMAIN: The SMAD interaction motif is required for interaction with
CC SMAD2 and SMAD3 and the negative regulation of TGF-beta signaling.
CC {ECO:0000269|PubMed:20129061}.
CC -!- SIMILARITY: Belongs to the PMEPA1 family. {ECO:0000305}.
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; AF224278; AAF86322.1; -; mRNA.
DR EMBL; AF305616; AAL16781.1; -; mRNA.
DR EMBL; AY128643; AAM89277.1; -; mRNA.
DR EMBL; AF305426; AAL09357.1; -; Genomic_DNA.
DR EMBL; AL035541; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL121913; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471077; EAW75505.1; -; Genomic_DNA.
DR EMBL; CH471077; EAW75508.1; -; Genomic_DNA.
DR EMBL; BC015918; AAH15918.2; -; mRNA.
DR CCDS; CCDS13462.1; -. [Q969W9-2]
DR CCDS; CCDS13463.1; -. [Q969W9-1]
DR CCDS; CCDS13464.1; -. [Q969W9-3]
DR RefSeq; NP_001242905.1; NM_001255976.1.
DR RefSeq; NP_064567.2; NM_020182.4. [Q969W9-1]
DR RefSeq; NP_954638.1; NM_199169.2. [Q969W9-2]
DR RefSeq; NP_954639.1; NM_199170.2. [Q969W9-3]
DR RefSeq; NP_954640.1; NM_199171.2. [Q969W9-3]
DR AlphaFoldDB; Q969W9; -.
DR BioGRID; 121262; 57.
DR IntAct; Q969W9; 12.
DR MINT; Q969W9; -.
DR STRING; 9606.ENSP00000345826; -.
DR GlyGen; Q969W9; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q969W9; -.
DR PhosphoSitePlus; Q969W9; -.
DR BioMuta; PMEPA1; -.
DR DMDM; 20140695; -.
DR jPOST; Q969W9; -.
DR MassIVE; Q969W9; -.
DR PaxDb; Q969W9; -.
DR PeptideAtlas; Q969W9; -.
DR PRIDE; Q969W9; -.
DR ProteomicsDB; 73203; -.
DR Antibodypedia; 29054; 178 antibodies from 32 providers.
DR DNASU; 56937; -.
DR Ensembl; ENST00000265626.8; ENSP00000265626.4; ENSG00000124225.16. [Q969W9-3]
DR Ensembl; ENST00000341744.8; ENSP00000345826.3; ENSG00000124225.16. [Q969W9-1]
DR Ensembl; ENST00000347215.8; ENSP00000344014.4; ENSG00000124225.16. [Q969W9-2]
DR Ensembl; ENST00000395814.5; ENSP00000379159.1; ENSG00000124225.16. [Q969W9-3]
DR Ensembl; ENST00000395816.7; ENSP00000379161.3; ENSG00000124225.16. [Q969W9-3]
DR GeneID; 56937; -.
DR KEGG; hsa:56937; -.
DR MANE-Select; ENST00000341744.8; ENSP00000345826.3; NM_020182.5; NP_064567.2.
DR UCSC; uc002xyq.5; human. [Q969W9-1]
DR CTD; 56937; -.
DR DisGeNET; 56937; -.
DR GeneCards; PMEPA1; -.
DR HGNC; HGNC:14107; PMEPA1.
DR HPA; ENSG00000124225; Tissue enhanced (prostate).
DR MIM; 606564; gene.
DR neXtProt; NX_Q969W9; -.
DR OpenTargets; ENSG00000124225; -.
DR PharmGKB; PA162399822; -.
DR VEuPathDB; HostDB:ENSG00000124225; -.
DR eggNOG; ENOG502QRYK; Eukaryota.
DR GeneTree; ENSGT00390000000724; -.
DR InParanoid; Q969W9; -.
DR OMA; GISAMCY; -.
DR OrthoDB; 1189277at2759; -.
DR PhylomeDB; Q969W9; -.
DR TreeFam; TF331681; -.
DR PathwayCommons; Q969W9; -.
DR Reactome; R-HSA-2173788; Downregulation of TGF-beta receptor signaling.
DR SignaLink; Q969W9; -.
DR SIGNOR; Q969W9; -.
DR BioGRID-ORCS; 56937; 10 hits in 1074 CRISPR screens.
DR ChiTaRS; PMEPA1; human.
DR GeneWiki; TMEPAI; -.
DR GenomeRNAi; 56937; -.
DR Pharos; Q969W9; Tbio.
DR PRO; PR:Q969W9; -.
DR Proteomes; UP000005640; Chromosome 20.
DR RNAct; Q969W9; protein.
DR Bgee; ENSG00000124225; Expressed in visceral pleura and 191 other tissues.
DR ExpressionAtlas; Q969W9; baseline and differential.
DR Genevisible; Q969W9; HS.
DR GO; GO:0031901; C:early endosome membrane; IDA:UniProtKB.
DR GO; GO:0010008; C:endosome membrane; IDA:UniProtKB.
DR GO; GO:0000139; C:Golgi membrane; IDA:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; NAS:UniProtKB.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:HPA.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0070412; F:R-SMAD binding; IPI:UniProtKB.
DR GO; GO:0050699; F:WW domain binding; IPI:UniProtKB.
DR GO; GO:0030521; P:androgen receptor signaling pathway; NAS:UniProtKB.
DR GO; GO:0060394; P:negative regulation of pathway-restricted SMAD protein phosphorylation; IDA:UniProtKB.
DR GO; GO:0010991; P:negative regulation of SMAD protein complex assembly; IDA:UniProtKB.
DR GO; GO:0030512; P:negative regulation of transforming growth factor beta receptor signaling pathway; IDA:UniProtKB.
DR InterPro; IPR039122; TMEPAI.
DR InterPro; IPR043445; TMEPAI/LRAD4.
DR PANTHER; PTHR16514; PTHR16514; 1.
DR PANTHER; PTHR16514:SF5; PTHR16514:SF5; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Endosome; Golgi apparatus; Membrane;
KW Reference proteome; Repeat; Signal transduction inhibitor; Transmembrane;
KW Transmembrane helix; Ubl conjugation pathway.
FT CHAIN 1..287
FT /note="Protein TMEPAI"
FT /id="PRO_0000185442"
FT TOPO_DOM 1..40
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT TRANSMEM 41..63
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 64..287
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT REGION 239..258
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 158..161
FT /note="PPxY motif 1"
FT MOTIF 186..189
FT /note="SMAD interaction motif (SIM)"
FT MOTIF 229..232
FT /note="PPxY motif 2"
FT COMPBIAS 239..255
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT VAR_SEQ 1..50
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:12670906"
FT /id="VSP_044588"
FT VAR_SEQ 1..37
FT /note="MHRLMGVNSTAAAAAGQPNVSCTCNCKRSLFQSMEIT -> MA (in
FT isoform 2)"
FT /evidence="ECO:0000303|PubMed:10873380"
FT /id="VSP_006438"
FT VARIANT 128
FT /note="E -> D (in dbSNP:rs41314918)"
FT /id="VAR_062154"
FT MUTAGEN 161
FT /note="Y->A: Impairs interaction with NEDD4. Impairs
FT polyubiquitination of AR; when associated with A-232."
FT /evidence="ECO:0000269|PubMed:12907594,
FT ECO:0000269|PubMed:18703514"
FT MUTAGEN 232
FT /note="Y->A: Impairs interaction with NEDD4. Impairs
FT polyubiquitination of AR; when associated with A-232."
FT /evidence="ECO:0000269|PubMed:12907594,
FT ECO:0000269|PubMed:18703514"
SQ SEQUENCE 287 AA; 31609 MW; 6103473561AE08DA CRC64;
MHRLMGVNST AAAAAGQPNV SCTCNCKRSL FQSMEITELE FVQIIIIVVV MMVMVVVITC
LLSHYKLSAR SFISRHSQGR RREDALSSEG CLWPSESTVS GNGIPEPQVY APPRPTDRLA
VPPFAQRERF HRFQPTYPYL QHEIDLPPTI SLSDGEEPPP YQGPCTLQLR DPEQQLELNR
ESVRAPPNRT IFDSDLMDSA RLGGPCPPSS NSGISATCYG SGGRMEGPPP TYSEVIGHYP
GSSFQHQQSS GPPSLLEGTR LHHTHIAPLE SAAIWSKEKD KQKGHPL
