NFIP2_MOUSE
ID NFIP2_MOUSE Reviewed; 311 AA.
AC Q91ZP6; Q5DTZ9; Q6IR02; Q8BVC5;
DT 30-AUG-2005, integrated into UniProtKB/Swiss-Prot.
DT 30-AUG-2005, sequence version 2.
DT 25-MAY-2022, entry version 121.
DE RecName: Full=NEDD4 family-interacting protein 2;
DE AltName: Full=NEDD4 WW domain-binding protein 5A;
DE Flags: Fragment;
GN Name=Ndfip2; Synonyms=Kiaa1165, N4wbp5A;
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] (ISOFORM 1).
RC STRAIN=FVB/N-3; TISSUE=Mammary gland;
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 [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 5-311 (ISOFORM 1).
RC STRAIN=C57BL/6J; TISSUE=Cecum, Forelimb, and Spinal cord;
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 [3]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 71-311 (ISOFORM 1), FUNCTION, INTERACTION
RP WITH NEDD4 AND NEDD4L, TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION.
RC STRAIN=CBA/J; TISSUE=Brain;
RX PubMed=12050153; DOI=10.1074/jbc.m203018200;
RA Konstas A.-A., Shearwin-Whyatt L.M., Fotia A.B., Degger B., Riccardi D.,
RA Cook D.I., Korbmacher C., Kumar S.;
RT "Regulation of the epithelial sodium channel by N4WBP5A, a novel
RT Nedd4/Nedd4-2-interacting protein.";
RL J. Biol. Chem. 277:29406-29416(2002).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 158-311 (ISOFORM 2).
RC TISSUE=Embryonic intestine;
RA Okazaki N., Kikuno R.F., Ohara R., Inamoto S., Nagase T., Ohara O.,
RA Koga H.;
RT "Prediction of the coding sequences of mouse homologues of KIAA gene. The
RT complete nucleotide sequences of mouse KIAA-homologous cDNAs identified by
RT screening of terminal sequences of cDNA clones randomly sampled from size-
RT fractionated libraries.";
RL Submitted (FEB-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP FUNCTION, INTERACTION WITH NEDD4, SUBCELLULAR LOCATION, AND UBIQUITINATION.
RX PubMed=15252135; DOI=10.1242/jcs.01212;
RA Shearwin-Whyatt L.M., Brown D.L., Wylie F.G., Stow J.L., Kumar S.;
RT "N4WBP5A (Ndfip2), a Nedd4-interacting protein, localizes to multivesicular
RT bodies and the Golgi, and has a potential role in protein trafficking.";
RL J. Cell Sci. 117:3679-3689(2004).
RN [6]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=27088444; DOI=10.1038/ncomms11226;
RA O'Leary C.E., Riling C.R., Spruce L.A., Ding H., Kumar S., Deng G., Liu Y.,
RA Seeholzer S.H., Oliver P.M.;
RT "Ndfip-mediated degradation of Jak1 tunes cytokine signalling to limit
RT expansion of CD4+ effector T cells.";
RL Nat. Commun. 7:11226-11226(2016).
CC -!- FUNCTION: Activates HECT domain-containing E3 ubiquitin-protein
CC ligases, including ITCH, NEDD4, NEDD4L, SMURF2, WWP1 and WWP2, and
CC consequently modulates the stability of their targets. As a result, may
CC control many cellular processes. Recruits ITCH, NEDD4 and SMURF2 to
CC endosomal membranes. Negatively regulates KCNH2 potassium channel
CC activity by decreasing its cell-surface expression and interfering with
CC channel maturation through recruitment of NEDD4L to the Golgi apparatus
CC and multivesicular body where it mediates KCNH2 degradation (By
CC similarity). May modulate EGFR signaling (By similarity). Together with
CC NDFIP1, limits the cytokine signaling and expansion of effector Th2 T-
CC cells by promoting degradation of JAK1, probably by ITCH- and NEDD4L-
CC mediated ubiquitination (PubMed:27088444).
CC {ECO:0000250|UniProtKB:Q9NV92, ECO:0000269|PubMed:12050153,
CC ECO:0000269|PubMed:15252135, ECO:0000269|PubMed:27088444}.
CC -!- SUBUNIT: Forms heterodimers with NDFIP1 (By similarity). Interacts with
CC HECT domain-containing E3 ubiquitin-protein ligases, including NEDD4
CC (PubMed:12050153, PubMed:15252135). Interacts with NEDD4L
CC (PubMed:12050153). When phosphorylated at Tyr-142, interacts with SRC
CC and LYN SH2 domain (By similarity). May thus act as a scaffold that
CC recruits SRC to NDFIP1, enhancing NDFIP1 phosphorylation (By
CC similarity). Interacts with SLC11A2/DMT1 (By similarity). May interact
CC with phosphorylated EGFR (By similarity). Interacts with KCNH2 (By
CC similarity). {ECO:0000250|UniProtKB:Q9NV92,
CC ECO:0000269|PubMed:12050153, ECO:0000269|PubMed:15252135}.
CC -!- SUBCELLULAR LOCATION: Endosome membrane {ECO:0000269|PubMed:12050153};
CC Multi-pass membrane protein {ECO:0000269|PubMed:12050153}. Golgi
CC apparatus membrane {ECO:0000269|PubMed:15252135}. Endosome,
CC multivesicular body membrane {ECO:0000269|PubMed:15252135}; Multi-pass
CC membrane protein {ECO:0000269|PubMed:15252135}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q91ZP6-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q91ZP6-2; Sequence=VSP_015438, VSP_015439;
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed, with highest levels in
CC brain, liver, kidney and testis. {ECO:0000269|PubMed:12050153}.
CC -!- DOMAIN: The PPxY motifs are required for E3 ubiquitin-protein ligase
CC activation and for ubiquitination. {ECO:0000250}.
CC -!- PTM: Ubiquitinated by NEDD4 and NEDD4L; which does not affect turnover
CC (Probable). Also ubiquitinated by ITCH (By similarity). {ECO:0000250,
CC ECO:0000305}.
CC -!- PTM: Undergoes transient tyrosine-phosphorylation following EGF
CC stimulation, most probably catalyzed by SRC. Phosphorylation on Tyr-
CC 126, Tyr-146 and Tyr-152 are dependent on the phosphorylation on Tyr-
CC 142. Also phosphorylated by LYN and FYN (By similarity).
CC {ECO:0000250|UniProtKB:Q9NV92}.
CC -!- DISRUPTION PHENOTYPE: Mutant mice show no signs of inflammation and
CC have normal T-cell populations in thymus, lymph nodes and spleen.
CC {ECO:0000269|PubMed:27088444}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH71237.1; Type=Erroneous initiation; Evidence={ECO:0000305};
CC Sequence=BAC27240.1; Type=Erroneous initiation; Evidence={ECO:0000305};
CC Sequence=BAC33869.1; Type=Erroneous initiation; Evidence={ECO:0000305};
CC Sequence=BAC37471.1; Type=Erroneous initiation; Evidence={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; BC071237; AAH71237.1; ALT_INIT; mRNA.
DR EMBL; AK031073; BAC27240.1; ALT_INIT; mRNA.
DR EMBL; AK049678; BAC33869.1; ALT_INIT; mRNA.
DR EMBL; AK078939; BAC37471.1; ALT_INIT; mRNA.
DR EMBL; AF411608; AAL05872.1; -; mRNA.
DR EMBL; AK220371; BAD90430.1; -; mRNA.
DR AlphaFoldDB; Q91ZP6; -.
DR DIP; DIP-58955N; -.
DR IntAct; Q91ZP6; 1.
DR STRING; 10090.ENSMUSP00000137875; -.
DR TCDB; 8.A.30.1.1; the nedd4-family interacting protein-2 (nedd4) family.
DR iPTMnet; Q91ZP6; -.
DR PhosphoSitePlus; Q91ZP6; -.
DR SwissPalm; Q91ZP6; -.
DR MaxQB; Q91ZP6; -.
DR PaxDb; Q91ZP6; -.
DR PRIDE; Q91ZP6; -.
DR ProteomicsDB; 252816; -. [Q91ZP6-1]
DR ProteomicsDB; 252817; -. [Q91ZP6-2]
DR MGI; MGI:1923523; Ndfip2.
DR eggNOG; KOG4812; Eukaryota.
DR InParanoid; Q91ZP6; -.
DR OMA; NMTENMA; -.
DR PhylomeDB; Q91ZP6; -.
DR ChiTaRS; Ndfip2; mouse.
DR Proteomes; UP000000589; Unplaced.
DR RNAct; Q91ZP6; protein.
DR GO; GO:0005737; C:cytoplasm; ISO:MGI.
DR GO; GO:0005783; C:endoplasmic reticulum; ISO:MGI.
DR GO; GO:0005794; C:Golgi apparatus; ISO:MGI.
DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; ISM:MGI.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; ISO:MGI.
DR GO; GO:0005739; C:mitochondrion; ISO:MGI.
DR GO; GO:0032585; C:multivesicular body membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; ISO:MGI.
DR GO; GO:0050699; F:WW domain binding; ISO:MGI.
DR GO; GO:0030001; P:metal ion transport; IBA:GO_Central.
DR GO; GO:0010629; P:negative regulation of gene expression; ISO:MGI.
DR GO; GO:0051224; P:negative regulation of protein transport; ISO:MGI.
DR GO; GO:0032410; P:negative regulation of transporter activity; ISO:MGI.
DR GO; GO:0031398; P:positive regulation of protein ubiquitination; ISO:MGI.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IBA:GO_Central.
DR GO; GO:0007034; P:vacuolar transport; IEA:InterPro.
DR InterPro; IPR019325; NEDD4/Bsd2.
DR PANTHER; PTHR13396; PTHR13396; 1.
DR Pfam; PF10176; DUF2370; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Endosome; Golgi apparatus; Membrane; Phosphoprotein;
KW Reference proteome; Transmembrane; Transmembrane helix; Ubl conjugation.
FT CHAIN <1..311
FT /note="NEDD4 family-interacting protein 2"
FT /id="PRO_0000096795"
FT TOPO_DOM <1..206
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 207..227
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 228..232
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 233..253
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 254..262
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 263..283
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 284..311
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT REGION 1..133
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 123..126
FT /note="Interaction with NEDD4"
FT /evidence="ECO:0000305"
FT MOTIF 123..126
FT /note="PPxY motif 1"
FT MOTIF 149..152
FT /note="PPxY motif 2"
FT MOTIF 159..161
FT /note="PPxY motif 3"
FT COMPBIAS 49..74
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 93..108
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 126
FT /note="Phosphotyrosine; by SRC"
FT /evidence="ECO:0000250|UniProtKB:Q9NV92"
FT MOD_RES 142
FT /note="Phosphotyrosine; by SRC"
FT /evidence="ECO:0000250|UniProtKB:Q9NV92"
FT MOD_RES 146
FT /note="Phosphotyrosine; by SRC"
FT /evidence="ECO:0000250|UniProtKB:Q9NV92"
FT MOD_RES 152
FT /note="Phosphotyrosine; by SRC"
FT /evidence="ECO:0000250|UniProtKB:Q9NV92"
FT VAR_SEQ 256..263
FT /note="FSDYFTGY -> VSILIIFM (in isoform 2)"
FT /evidence="ECO:0000303|Ref.4"
FT /id="VSP_015438"
FT VAR_SEQ 264..311
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|Ref.4"
FT /id="VSP_015439"
FT CONFLICT 38
FT /note="S -> T (in Ref. 2; BAC33869)"
FT /evidence="ECO:0000305"
FT CONFLICT 70
FT /note="R -> S (in Ref. 2; BAC27240)"
FT /evidence="ECO:0000305"
FT CONFLICT 113
FT /note="A -> T (in Ref. 1; AAH71237)"
FT /evidence="ECO:0000305"
FT CONFLICT 298
FT /note="S -> G (in Ref. 2; BAC37471)"
FT /evidence="ECO:0000305"
FT NON_TER 1
SQ SEQUENCE 311 AA; 33638 MW; AC9A445A83F1B789 CRC64;
RRSASDAELS AGAEGATGSE AAPPGDLGGR TRGGGRGSAA AAATTSTREA EGAERRGDTP
ARKPDPEAGR MDHHQLGTGR YQVLHNEEDN SESSAVEQPS TSSLAAPTVE AAASAPALDP
DSPPPYSSIT VEAPTTSDTD VYSEFYPVPP PYSVATSLPT YDEAEKAKAA ALAAAAADAP
QRNQEEDCTP RDDFSDVEQL RVGNDGIFML AFFMAFIFNW LGFCLSFCIT NTIAGRYGAI
CGFGLSLIKW ILIVRFSDYF TGYFNGQYWL WWIFLVLGLL LFFRGFVNYL KVRNMSESMA
AAHRTRYFFL L
