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Protein

Protein TMEPAI

Gene

PMEPA1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Functions as a negative regulator of TGF-beta signaling and thereby probably plays a role in cell proliferation, differentiation, apoptosis, motility, extracellular matrix production and immunosuppression. In the canonical TGF-beta pathway, ZFYVE9/SARA recruits the intracellular signal transducer and transcriptional modulators SMAD2 and SMAD3 to the TGF-beta receptor. Phosphorylated by the receptor, SMAD2 and SMAD3 then form a heteromeric complex with SMAD4 that translocates to the nucleus to regulate transcription. Through interaction with SMAD2 and SMAD3, LDLRAD4 may compete with ZFYVE9 and SMAD4 and prevent propagation of the intracellular signal (PubMed:20129061, PubMed:24627487). Also involved in down-regulation of the androgen receptor (AR), enhancing ubiquitination and proteasome-mediated degradation of AR, probably by recruiting NEDD4 (PubMed:18703514).3 Publications

GO - Molecular functioni

  • R-SMAD binding Source: UniProtKB
  • WW domain binding Source: UniProtKB

GO - Biological processi

  • androgen receptor signaling pathway Source: UniProtKB
  • negative regulation of pathway-restricted SMAD protein phosphorylation Source: UniProtKB
  • negative regulation of SMAD protein complex assembly Source: UniProtKB
  • negative regulation of transforming growth factor beta receptor signaling pathway Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Signal transduction inhibitor

Keywords - Biological processi

Ubl conjugation pathway

Enzyme and pathway databases

ReactomeiR-HSA-2173788. Downregulation of TGF-beta receptor signaling.

Names & Taxonomyi

Protein namesi
Recommended name:
Protein TMEPAI
Alternative name(s):
Prostate transmembrane protein androgen induced 1
Solid tumor-associated 1 protein
Transmembrane prostate androgen-induced protein
Gene namesi
Name:PMEPA1
Synonyms:STAG1, TMEPAI
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 20

Organism-specific databases

HGNCiHGNC:14107. PMEPA1.

Subcellular locationi

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini1 – 4040LumenalSequence analysisAdd
BLAST
Transmembranei41 – 6323HelicalSequence analysisAdd
BLAST
Topological domaini64 – 287224CytoplasmicSequence analysisAdd
BLAST

GO - Cellular componenti

  • early endosome membrane Source: UniProtKB
  • endosome membrane Source: UniProtKB
  • Golgi membrane Source: UniProtKB
  • integral component of membrane Source: UniProtKB
  • intracellular membrane-bounded organelle Source: HPA
  • nucleoplasm Source: HPA
  • plasma membrane Source: Reactome
Complete GO annotation...

Keywords - Cellular componenti

Endosome, Golgi apparatus, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi161 – 1611Y → A: Impairs interaction with NEDD4. Impairs polyubiquitination of AR; when associated with A-232. 2 Publications
Mutagenesisi232 – 2321Y → A: Impairs interaction with NEDD4. Impairs polyubiquitination of AR; when associated with A-232. 2 Publications

Organism-specific databases

PharmGKBiPA162399822.

Polymorphism and mutation databases

BioMutaiPMEPA1.
DMDMi20140695.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 287287Protein TMEPAIPRO_0000185442Add
BLAST

Proteomic databases

PaxDbiQ969W9.
PeptideAtlasiQ969W9.
PRIDEiQ969W9.

PTM databases

iPTMnetiQ969W9.
PhosphoSiteiQ969W9.

Expressioni

Tissue specificityi

Highest expression in prostate. Also expressed in ovary.

Inductioni

Up-regulated by androgen and TGF-beta (at protein level).2 Publications

Gene expression databases

BgeeiQ969W9.
CleanExiHS_PMEPA1.
HS_STAG1.
ExpressionAtlasiQ969W9. baseline and differential.
GenevisibleiQ969W9. HS.

Interactioni

Subunit structurei

Interacts with NEDD4 (WW-binding motifs). Interacts with AR. Interacts with LDLRAD4. Interacts (via the SMAD interaction motif) with SMAD2 and SMAD3.4 Publications

GO - Molecular functioni

  • R-SMAD binding Source: UniProtKB
  • WW domain binding Source: UniProtKB

Protein-protein interaction databases

BioGridi121262. 6 interactions.
IntActiQ969W9. 2 interactions.
MINTiMINT-4829946.
STRINGi9606.ENSP00000345826.

Structurei

3D structure databases

ProteinModelPortaliQ969W9.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi158 – 1614WW-binding 1
Motifi186 – 1894SMAD interaction motif (SIM)
Motifi229 – 2324WW-binding 2

Domaini

The WW-binding motifs mediate interaction with NEDD4.1 Publication
The SMAD interaction motif is required for interaction with SMAD2 and SMAD3 and the negative regulation of TGF-beta signaling.1 Publication

Sequence similaritiesi

Belongs to the PMEPA1 family.Curated

Keywords - Domaini

Repeat, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiENOG410IEW4. Eukaryota.
ENOG4111QDT. LUCA.
GeneTreeiENSGT00390000000724.
HOGENOMiHOG000276535.
HOVERGENiHBG059833.
InParanoidiQ969W9.
OMAiWSKEKDK.
OrthoDBiEOG7PK91C.
PhylomeDBiQ969W9.
TreeFamiTF331681.

Sequences (3)i

Sequence statusi: Complete.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q969W9-1) [UniParc]FASTAAdd to basket

Also known as: a

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MHRLMGVNST AAAAAGQPNV SCTCNCKRSL FQSMEITELE FVQIIIIVVV
60 70 80 90 100
MMVMVVVITC LLSHYKLSAR SFISRHSQGR RREDALSSEG CLWPSESTVS
110 120 130 140 150
GNGIPEPQVY APPRPTDRLA VPPFAQRERF HRFQPTYPYL QHEIDLPPTI
160 170 180 190 200
SLSDGEEPPP YQGPCTLQLR DPEQQLELNR ESVRAPPNRT IFDSDLMDSA
210 220 230 240 250
RLGGPCPPSS NSGISATCYG SGGRMEGPPP TYSEVIGHYP GSSFQHQQSS
260 270 280
GPPSLLEGTR LHHTHIAPLE SAAIWSKEKD KQKGHPL
Length:287
Mass (Da):31,609
Last modified:December 1, 2001 - v1
Checksum:i6103473561AE08DA
GO
Isoform 2 (identifier: Q969W9-2) [UniParc]FASTAAdd to basket

Also known as: b

The sequence of this isoform differs from the canonical sequence as follows:
     1-37: MHRLMGVNSTAAAAAGQPNVSCTCNCKRSLFQSMEIT → MA

Show »
Length:252
Mass (Da):27,900
Checksum:i0864B9DAB8A21959
GO
Isoform 3 (identifier: Q969W9-3) [UniParc]FASTAAdd to basket

Also known as: c

The sequence of this isoform differs from the canonical sequence as follows:
     1-50: Missing.

Show »
Length:237
Mass (Da):26,201
Checksum:iA44A274EAABFD930
GO

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti128 – 1281E → D.
Corresponds to variant rs41314918 [ dbSNP | Ensembl ].
VAR_062154

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei1 – 5050Missing in isoform 3. 1 PublicationVSP_044588Add
BLAST
Alternative sequencei1 – 3737MHRLM…SMEIT → MA in isoform 2. 1 PublicationVSP_006438Add
BLAST

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF224278 mRNA. Translation: AAF86322.1.
AF305616 mRNA. Translation: AAL16781.1.
AY128643 mRNA. Translation: AAM89277.1.
AF305426 Genomic DNA. Translation: AAL09357.1.
AL035541, AL121913 Genomic DNA. Translation: CAI23105.1.
AL121913, AL035541 Genomic DNA. Translation: CAI19031.1.
AL121913, AL035541 Genomic DNA. Translation: CAM27272.1.
AL035541, AL121913 Genomic DNA. Translation: CAM28295.1.
CH471077 Genomic DNA. Translation: EAW75505.1.
CH471077 Genomic DNA. Translation: EAW75508.1.
BC015918 mRNA. Translation: AAH15918.2.
CCDSiCCDS13462.1. [Q969W9-2]
CCDS13463.1. [Q969W9-1]
CCDS13464.1. [Q969W9-3]
RefSeqiNP_001242905.1. NM_001255976.1.
NP_064567.2. NM_020182.4. [Q969W9-1]
NP_954638.1. NM_199169.2. [Q969W9-2]
NP_954639.1. NM_199170.2. [Q969W9-3]
NP_954640.1. NM_199171.2. [Q969W9-3]
UniGeneiHs.517155.

Genome annotation databases

EnsembliENST00000265626; ENSP00000265626; ENSG00000124225. [Q969W9-3]
ENST00000341744; ENSP00000345826; ENSG00000124225. [Q969W9-1]
ENST00000347215; ENSP00000344014; ENSG00000124225. [Q969W9-2]
ENST00000395814; ENSP00000379159; ENSG00000124225. [Q969W9-3]
ENST00000395816; ENSP00000379161; ENSG00000124225. [Q969W9-3]
GeneIDi56937.
KEGGihsa:56937.
UCSCiuc002xyq.5. human. [Q969W9-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF224278 mRNA. Translation: AAF86322.1.
AF305616 mRNA. Translation: AAL16781.1.
AY128643 mRNA. Translation: AAM89277.1.
AF305426 Genomic DNA. Translation: AAL09357.1.
AL035541, AL121913 Genomic DNA. Translation: CAI23105.1.
AL121913, AL035541 Genomic DNA. Translation: CAI19031.1.
AL121913, AL035541 Genomic DNA. Translation: CAM27272.1.
AL035541, AL121913 Genomic DNA. Translation: CAM28295.1.
CH471077 Genomic DNA. Translation: EAW75505.1.
CH471077 Genomic DNA. Translation: EAW75508.1.
BC015918 mRNA. Translation: AAH15918.2.
CCDSiCCDS13462.1. [Q969W9-2]
CCDS13463.1. [Q969W9-1]
CCDS13464.1. [Q969W9-3]
RefSeqiNP_001242905.1. NM_001255976.1.
NP_064567.2. NM_020182.4. [Q969W9-1]
NP_954638.1. NM_199169.2. [Q969W9-2]
NP_954639.1. NM_199170.2. [Q969W9-3]
NP_954640.1. NM_199171.2. [Q969W9-3]
UniGeneiHs.517155.

3D structure databases

ProteinModelPortaliQ969W9.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi121262. 6 interactions.
IntActiQ969W9. 2 interactions.
MINTiMINT-4829946.
STRINGi9606.ENSP00000345826.

PTM databases

iPTMnetiQ969W9.
PhosphoSiteiQ969W9.

Polymorphism and mutation databases

BioMutaiPMEPA1.
DMDMi20140695.

Proteomic databases

PaxDbiQ969W9.
PeptideAtlasiQ969W9.
PRIDEiQ969W9.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000265626; ENSP00000265626; ENSG00000124225. [Q969W9-3]
ENST00000341744; ENSP00000345826; ENSG00000124225. [Q969W9-1]
ENST00000347215; ENSP00000344014; ENSG00000124225. [Q969W9-2]
ENST00000395814; ENSP00000379159; ENSG00000124225. [Q969W9-3]
ENST00000395816; ENSP00000379161; ENSG00000124225. [Q969W9-3]
GeneIDi56937.
KEGGihsa:56937.
UCSCiuc002xyq.5. human. [Q969W9-1]

Organism-specific databases

CTDi56937.
GeneCardsiPMEPA1.
HGNCiHGNC:14107. PMEPA1.
MIMi606564. gene.
neXtProtiNX_Q969W9.
PharmGKBiPA162399822.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiENOG410IEW4. Eukaryota.
ENOG4111QDT. LUCA.
GeneTreeiENSGT00390000000724.
HOGENOMiHOG000276535.
HOVERGENiHBG059833.
InParanoidiQ969W9.
OMAiWSKEKDK.
OrthoDBiEOG7PK91C.
PhylomeDBiQ969W9.
TreeFamiTF331681.

Enzyme and pathway databases

ReactomeiR-HSA-2173788. Downregulation of TGF-beta receptor signaling.

Miscellaneous databases

ChiTaRSiPMEPA1. human.
GeneWikiiTMEPAI.
GenomeRNAii56937.
PROiQ969W9.
SOURCEiSearch...

Gene expression databases

BgeeiQ969W9.
CleanExiHS_PMEPA1.
HS_STAG1.
ExpressionAtlasiQ969W9. baseline and differential.
GenevisibleiQ969W9. HS.

Family and domain databases

ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "A novel androgen-regulated gene, PMEPA1, located on chromosome 20q13 exhibits high level expression in prostate."
    Xu L.L., Shanmugam N., Segawa T., Sesterhenn I.A., McLeod D.G., Moul J.W., Srivastava S.
    Genomics 66:257-263(2000) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
  2. "Characterization of a novel gene, STAG1/PMEPA1, upregulated in renal cell carcinoma and other solid tumors."
    Rae F.K., Hooper J.D., Nicol D.L., Clements J.A.
    Mol. Carcinog. 32:44-53(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
  3. "PMEPA1, a transforming growth factor-beta-induced marker of terminal colonocyte differentiation whose expression is maintained in primary and metastatic colon cancer."
    Brunschwig E.B., Wilson K., Mack D., Dawson D., Lawrence E., Willson J.K.V., Lu S., Nosrati A., Rerko R.M., Swinler S., Beard L., Lutterbaugh J.D., Willis J., Platzer P., Markowitz S.
    Cancer Res. 63:1568-1575(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
  4. "The DNA sequence and comparative analysis of human chromosome 20."
    Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R., Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L., Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M., Beasley O.P., Bird C.P., Blakey S.E.
    , Bridgeman A.M., Brown A.J., Buck D., Burrill W.D., Butler A.P., Carder C., Carter N.P., Chapman J.C., Clamp M., Clark G., Clark L.N., Clark S.Y., Clee C.M., Clegg S., Cobley V.E., Collier R.E., Connor R.E., Corby N.R., Coulson A., Coville G.J., Deadman R., Dhami P.D., Dunn M., Ellington A.G., Frankland J.A., Fraser A., French L., Garner P., Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E., Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J., Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D., Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S., Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D., Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A., Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T., Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I., Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H., Rice C.M., Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., Skuce C.D., Smith M.L., Soderlund C., Steward C.A., Sulston J.E., Swann R.M., Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., Tracey A., Tromans A.C., Vaudin M., Wall M., Wallis J.M., Whitehead S.L., Whittaker P., Willey D.L., Williams L., Williams S.A., Wilming L., Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., Rogers J.
    Nature 414:865-871(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
  5. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
  6. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 8-287 (ISOFORM 1).
    Tissue: Kidney.
  7. "PMEPA1, an androgen-regulated NEDD4-binding protein, exhibits cell growth inhibitory function and decreased expression during prostate cancer progression."
    Xu L.L., Shi Y., Petrovics G., Sun C., Makarem M., Zhang W., Sesterhenn I.A., McLeod D.G., Sun L., Moul J.W., Srivastava S.
    Cancer Res. 63:4299-4304(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH NEDD4, MUTAGENESIS OF TYR-161 AND TYR-232.
  8. "A feedback loop between the androgen receptor and a NEDD4-binding protein, PMEPA1, in prostate cancer cells."
    Li H., Xu L.L., Masuda K., Raymundo E., McLeod D.G., Dobi A., Srivastava S.
    J. Biol. Chem. 283:28988-28995(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, INTERACTION WITH AR, MOTIFS, MUTAGENESIS OF TYR-161 AND TYR-232, INDUCTION BY ANDROGEN.
  9. "TMEPAI, a transmembrane TGF-beta-inducible protein, sequesters Smad proteins from active participation in TGF-beta signaling."
    Watanabe Y., Itoh S., Goto T., Ohnishi E., Inamitsu M., Itoh F., Satoh K., Wiercinska E., Yang W., Shi L., Tanaka A., Nakano N., Mommaas A.M., Shibuya H., Ten Dijke P., Kato M.
    Mol. Cell 37:123-134(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, INTERACTION WITH SMAD2 AND SMAD3, SUBCELLULAR LOCATION, MOTIF, INDUCTION BY TGF-BETA.
  10. Cited for: FUNCTION, INTERACTION WITH LDLRAD4, SUBCELLULAR LOCATION.

Entry informationi

Entry nameiPMEPA_HUMAN
AccessioniPrimary (citable) accession number: Q969W9
Secondary accession number(s): Q5TDR6
, Q8NER4, Q96B72, Q9UJD3
Entry historyi
Integrated into UniProtKB/Swiss-Prot: March 5, 2002
Last sequence update: December 1, 2001
Last modified: July 6, 2016
This is version 120 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human chromosome 20
    Human chromosome 20: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.