PMEPA_MOUSE
ID PMEPA_MOUSE Reviewed; 260 AA.
AC Q9D7R2; Q9EQH9;
DT 05-MAR-2002, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2001, sequence version 1.
DT 25-MAY-2022, entry version 106.
DE RecName: Full=Protein TMEPAI;
DE AltName: Full=NEDD4 WW domain-binding protein 4;
DE AltName: Full=Prostate transmembrane protein androgen induced 1;
DE AltName: Full=Transmembrane prostate androgen-induced protein;
GN Name=Pmepa1; Synonyms=N4wbp4, Tmepai;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Stomach;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 59-260, INTERACTION WITH NEDD4, PPXY MOTIFS,
RP AND MUTAGENESIS OF TYR-139 AND TYR-210.
RX PubMed=11042109; DOI=10.1042/bj3510557;
RA Jolliffe C.N., Harvey K.F., Haines B.P., Parasivam G., Kumar S.;
RT "Identification of multiple proteins expressed in murine embryos as binding
RT partners for the WW domains of the ubiquitin-protein ligase Nedd4.";
RL Biochem. J. 351:557-565(2000).
RN [3]
RP FUNCTION.
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 [4]
RP TISSUE SPECIFICITY.
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). Also involved in down-regulation of the androgen
CC receptor (AR), enhancing ubiquitination and proteasome-mediated
CC degradation of AR, probably by recruiting NEDD4.
CC {ECO:0000269|PubMed:20129061}.
CC -!- SUBUNIT: Interacts with AR. Interacts with LDLRAD4. Interacts (via the
CC SMAD interaction motif) with SMAD2 and SMAD3 (By similarity). Interacts
CC with NEDD4 (via PPxY motifs). {ECO:0000250,
CC ECO:0000269|PubMed:11042109}.
CC -!- INTERACTION:
CC Q9D7R2; P46935: Nedd4; NbExp=5; IntAct=EBI-6304097, EBI-773516;
CC -!- SUBCELLULAR LOCATION: Early endosome membrane {ECO:0000250}; Single-
CC pass membrane protein {ECO:0000250}. Golgi apparatus membrane
CC {ECO:0000250}; Single-pass membrane protein {ECO:0000250}.
CC -!- TISSUE SPECIFICITY: Expressed in brain, heart, kidney, bladder, ovary
CC and adrenal gland. {ECO:0000269|PubMed:24627487}.
CC -!- DOMAIN: The PPxY motifs mediate interaction with NEDD4.
CC {ECO:0000269|PubMed:11042109}.
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:0000250}.
CC -!- SIMILARITY: Belongs to the PMEPA1 family. {ECO:0000305}.
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DR EMBL; AK008976; BAB26001.1; -; mRNA.
DR EMBL; AF220208; AAG44247.1; -; mRNA.
DR AlphaFoldDB; Q9D7R2; -.
DR IntAct; Q9D7R2; 1.
DR STRING; 10090.ENSMUSP00000039950; -.
DR PhosphoSitePlus; Q9D7R2; -.
DR PaxDb; Q9D7R2; -.
DR PRIDE; Q9D7R2; -.
DR ProteomicsDB; 289635; -.
DR MGI; MGI:1929600; Pmepa1.
DR eggNOG; ENOG502QRYK; Eukaryota.
DR InParanoid; Q9D7R2; -.
DR Reactome; R-MMU-2173788; Downregulation of TGF-beta receptor signaling.
DR ChiTaRS; Pmepa1; mouse.
DR PRO; PR:Q9D7R2; -.
DR Proteomes; UP000000589; Unplaced.
DR RNAct; Q9D7R2; protein.
DR GO; GO:0031901; C:early endosome membrane; ISS:UniProtKB.
DR GO; GO:0010008; C:endosome membrane; ISS:UniProtKB.
DR GO; GO:0000139; C:Golgi membrane; ISS:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; ISO:MGI.
DR GO; GO:0070412; F:R-SMAD binding; ISO:MGI.
DR GO; GO:0050699; F:WW domain binding; ISO:MGI.
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; ISS: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 Endosome; Golgi apparatus; Membrane; Reference proteome; Repeat;
KW Signal transduction inhibitor; Transmembrane; Transmembrane helix;
KW Ubl conjugation pathway.
FT CHAIN 1..260
FT /note="Protein TMEPAI"
FT /id="PRO_0000185443"
FT TOPO_DOM 1..20
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT TRANSMEM 21..43
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 44..260
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT REGION 60..98
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 218..260
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 136..139
FT /note="PPxY motif 1"
FT MOTIF 164..167
FT /note="SMAD interaction motif (SIM)"
FT MOTIF 207..210
FT /note="PPxY motif 2"
FT COMPBIAS 218..235
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 241..260
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MUTAGEN 139
FT /note="Y->A: Alters interaction with NEDD4."
FT /evidence="ECO:0000269|PubMed:11042109"
FT MUTAGEN 210
FT /note="Y->A: Abolishes interaction with NEDD4."
FT /evidence="ECO:0000269|PubMed:11042109"
SQ SEQUENCE 260 AA; 28716 MW; 31AD07BD16B0D77D CRC64;
MSPARATAQR SLFPSMEITE LEFVQIVVIV VVMMVMVVMI TCLLSHYKLS ARSFISRHSQ
ARRRDDGLSS EGCLWPSEST VSGGMPEPQV YAPPRPTDRL AVPPFIQRSR FQPTYPYLQH
EIALPPTISL SDGEEPPPYQ GPCTLQLRDP EQQLELNRES VRAPPNRTIF DSDLIDSTML
GGPCPPSSNS GISATCYSSG GRMEGPPPTY SEVIGHYPGS SFQHQQSNGP SSLLEGTRLH
HSHIAPLENK EKEKQKGHPL
