NFIP1_RAT
ID NFIP1_RAT Reviewed; 221 AA.
AC Q5U2S1;
DT 06-DEC-2005, integrated into UniProtKB/Swiss-Prot.
DT 07-DEC-2004, sequence version 1.
DT 03-AUG-2022, entry version 102.
DE RecName: Full=NEDD4 family-interacting protein 1;
GN Name=Ndfip1; Synonyms=N4wbp5;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Heart;
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 SUBCELLULAR LOCATION.
RX PubMed=23897647; DOI=10.1093/cercor/bht191;
RA Hammond V.E., Gunnersen J.M., Goh C.P., Low L.H., Hyakumura T., Tang M.M.,
RA Britto J.M., Putz U., Howitt J.A., Tan S.S.;
RT "Ndfip1 is required for the development of pyramidal neuron dendrites and
RT spines in the neocortex.";
RL Cereb. Cortex 24:3289-3300(2014).
CC -!- FUNCTION: Activates HECT domain-containing E3 ubiquitin-protein
CC ligases, including NEDD4 and ITCH, and consequently modulates the
CC stability of their targets. As a result, controls many cellular
CC processes. Prevents chronic T-helper cell-mediated inflammation by
CC activating ITCH and thus controlling JUNB degradation. Promotes
CC pancreatic beta cell death through degradation of JUNB and inhibition
CC of the unfolded protein response, leading to reduction of insulin
CC secretion. Restricts the production of pro-inflammatory cytokines in
CC effector Th17 T-cells by promoting ITCH-mediated ubiquitination
CC degradation of RORC. Together with NDFIP2, limits the cytokine
CC signaling and expansion of effector Th2 T-cells by promoting
CC degradation of JAK1, probably by ITCH- and NEDD4L-mediated
CC ubiquitination. Regulates peripheral T-cell tolerance to self and
CC foreign antigens, forcing the exit of naive CD4+ T-cells from the cell
CC cycle before they become effector T-cells. Negatively regulates RLR-
CC mediated antiviral response by promoting SMURF1-mediated ubiquitination
CC and subsequent degradation of MAVS. Negatively regulates KCNH2
CC potassium channel activity by decreasing its cell-surface expression
CC and interfering with channel maturation through recruitment of NEDD4L
CC to the Golgi apparatus where it mediates KCNH2 degradation. In cortical
CC neurons, mediates the ubiquitination of the divalent metal transporter
CC SLC11A2/DMT1 by NEDD4L, leading to its down-regulation and protection
CC of the cells from cobalt and iron toxicity. Important for normal
CC development of dendrites and dendritic spines in cortex. Enhances the
CC ubiquitination of BRAT1 mediated by: NEDD4, NEDD4L and ITCH and is
CC required for the nuclear localization of ubiquitinated BRAT1. Enhances
CC the ITCH-mediated ubiquitination of MAP3K7 by recruiting E2 ubiquitin-
CC conjugating enzyme UBE2L3 to ITCH. Modulates EGFR signaling through
CC multiple pathways. In particular, may regulate the ratio of AKT1-to-
CC MAPK8 signaling in response to EGF, acting on AKT1 probably through
CC PTEN destabilization and on MAPK8 through ITCH-dependent MAP2K4
CC inactivation. As a result, may control cell growth rate. Inhibits cell
CC proliferation by promoting PTEN nuclear localization and changing its
CC signaling specificity. {ECO:0000250|UniProtKB:Q8R0W6,
CC ECO:0000250|UniProtKB:Q9BT67}.
CC -!- SUBUNIT: Forms heterodimers with NDFIP2. Interacts with several E3
CC ubiquitin-protein ligases, including ITCH, NEDD4, NEDD4L and WWP2. The
CC interaction with NEDD4, NEDD4L and ITCH leads to relocalization of
CC these proteins to exosomes and eventually to exosomal secretion.
CC Interacts with SR1402. Interacts with SLC11A2/DMT1. Interacts with
CC PTEN. May interact with phosphorylated EGFR. Interacts with BRAT1.
CC Interacts with KCNH2. Interacts with MAVS. Part of a complex containing
CC ITCH, NDFIP1 and MAP3K7. Interacts (via N-terminus) with UBE2L3; the
CC interaction mediates recruitment of UBE2L3 to ITCH.
CC {ECO:0000250|UniProtKB:Q8R0W6, ECO:0000250|UniProtKB:Q9BT67}.
CC -!- SUBCELLULAR LOCATION: Endosome membrane {ECO:0000250|UniProtKB:Q9BT67};
CC Multi-pass membrane protein {ECO:0000250|UniProtKB:Q9BT67}. Golgi
CC apparatus membrane {ECO:0000250|UniProtKB:Q9BT67}. Synapse, synaptosome
CC {ECO:0000250|UniProtKB:Q8R0W6}. Cell projection, dendrite
CC {ECO:0000269|PubMed:23897647}. Secreted {ECO:0000250|UniProtKB:Q9BT67}.
CC Note=Detected in exosomes and secreted via the exosomal pathway.
CC {ECO:0000250|UniProtKB:Q9BT67}.
CC -!- DOMAIN: The PPxY motifs are required for E3 ubiquitin-protein ligase
CC binding and activation and for ubiquitination. {ECO:0000250}.
CC -!- PTM: Ubiquitinated by NEDD4; mono-, di- and polyubiquitinated forms are
CC detected. Ubiquitination regulates its degradation (By similarity).
CC {ECO:0000250}.
CC -!- PTM: Undergoes transient tyrosine phosphorylation following EGF
CC stimulation, most probably by catalyzed by SRC. Phosphorylation SRC is
CC enhanced in the presence of NDFIP2 which may act as a scaffold to
CC recruit SRC to NDFIP1 (By similarity). {ECO:0000250}.
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DR EMBL; BC085887; AAH85887.1; -; mRNA.
DR RefSeq; NP_001013077.1; NM_001013059.1.
DR RefSeq; XP_006254695.1; XM_006254633.3.
DR AlphaFoldDB; Q5U2S1; -.
DR BioGRID; 253573; 2.
DR STRING; 10116.ENSRNOP00000018499; -.
DR iPTMnet; Q5U2S1; -.
DR PhosphoSitePlus; Q5U2S1; -.
DR PaxDb; Q5U2S1; -.
DR Ensembl; ENSRNOT00000018499; ENSRNOP00000018499; ENSRNOG00000013562.
DR GeneID; 291609; -.
DR KEGG; rno:291609; -.
DR UCSC; RGD:1310053; rat.
DR CTD; 80762; -.
DR RGD; 1310053; Ndfip1.
DR eggNOG; KOG4812; Eukaryota.
DR GeneTree; ENSGT00390000012721; -.
DR HOGENOM; CLU_074980_2_0_1; -.
DR InParanoid; Q5U2S1; -.
DR OMA; TGRQPHH; -.
DR OrthoDB; 1495850at2759; -.
DR PhylomeDB; Q5U2S1; -.
DR TreeFam; TF324911; -.
DR PRO; PR:Q5U2S1; -.
DR Proteomes; UP000002494; Chromosome 18.
DR Bgee; ENSRNOG00000013562; Expressed in Ammon's horn and 20 other tissues.
DR Genevisible; Q5U2S1; RN.
DR GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-KW.
DR GO; GO:0005938; C:cell cortex; ISO:RGD.
DR GO; GO:0030425; C:dendrite; IEA:UniProtKB-SubCell.
DR GO; GO:0005783; C:endoplasmic reticulum; IBA:GO_Central.
DR GO; GO:0010008; C:endosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0005794; C:Golgi apparatus; ISO:RGD.
DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; ISO:RGD.
DR GO; GO:0045202; C:synapse; IEA:UniProtKB-SubCell.
DR GO; GO:0050699; F:WW domain binding; ISO:RGD.
DR GO; GO:0006879; P:cellular iron ion homeostasis; ISO:RGD.
DR GO; GO:0030001; P:metal ion transport; IBA:GO_Central.
DR GO; GO:0010629; P:negative regulation of gene expression; ISO:RGD.
DR GO; GO:0050728; P:negative regulation of inflammatory response; ISO:RGD.
DR GO; GO:0032713; P:negative regulation of interleukin-4 production; ISO:RGD.
DR GO; GO:0048294; P:negative regulation of isotype switching to IgE isotypes; ISO:RGD.
DR GO; GO:0051224; P:negative regulation of protein transport; ISO:RGD.
DR GO; GO:0042130; P:negative regulation of T cell proliferation; ISO:RGD.
DR GO; GO:0032410; P:negative regulation of transporter activity; ISO:RGD.
DR GO; GO:0002829; P:negative regulation of type 2 immune response; ISO:RGD.
DR GO; GO:0045732; P:positive regulation of protein catabolic process; ISO:RGD.
DR GO; GO:0031398; P:positive regulation of protein ubiquitination; ISS:UniProtKB.
DR GO; GO:0048302; P:regulation of isotype switching to IgG isotypes; ISO:RGD.
DR GO; GO:0045619; P:regulation of lymphocyte differentiation; ISO:RGD.
DR GO; GO:0002761; P:regulation of myeloid leukocyte differentiation; ISO:RGD.
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 2: Evidence at transcript level;
KW Acetylation; Cell projection; Endosome; Golgi apparatus; Membrane;
KW Reference proteome; Repeat; Secreted; Synapse; Synaptosome; Transmembrane;
KW Transmembrane helix; Ubl conjugation.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:Q9BT67"
FT CHAIN 2..221
FT /note="NEDD4 family-interacting protein 1"
FT /id="PRO_0000076271"
FT TOPO_DOM 2..116
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 117..137
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 138..143
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 144..164
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 165..172
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 173..193
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 194..221
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT REGION 2..41
FT /note="Interaction with UBE2L3"
FT /evidence="ECO:0000250|UniProtKB:Q8R0W6"
FT REGION 15..45
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 42..76
FT /note="Interaction with ITCH"
FT /evidence="ECO:0000250|UniProtKB:Q8R0W6"
FT MOTIF 39..42
FT /note="PPxY motif 1"
FT MOTIF 64..67
FT /note="PPxY motif 2"
FT MOTIF 74..76
FT /note="PPxY motif 3"
FT MOD_RES 2
FT /note="N-acetylalanine"
FT /evidence="ECO:0000250|UniProtKB:Q9BT67"
SQ SEQUENCE 221 AA; 24913 MW; 96CA5183C1C17F0B CRC64;
MALALAALAA VEPACGTGYQ QLQNEEEPGE REQTAGDAPP PYSSISAESA AYFDYKDESG
FPKPPSYNVA TTLPSYDEAE RTKAEATIPL VPGRDEDFVG RDDFDDADQL RIGNDGIFML
TFFMAFLFNW IGFFLSFCLT TSAAGRYGAI SGFGLSLIKW ILIVRFSTYF PGYFDGQYWL
WWVFLVLGFL LFLRGFINYA KVRKMPETFS NLPRTRVLFI Y
