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Protein

NEDD4 family-interacting protein 1

Gene

Ndfip1

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Activates HECT domain-containing E3 ubiquitin-protein ligases, including NEDD4 and ITCH, and consequently modulates the stability of their targets. As a result, controls many cellular processes. Prevents chronic T-helper cell-mediated inflammation by activating ITCH and thus controlling JUNB degradation (PubMed:11748237, PubMed:17137798, PubMed:20962770). Promotes pancreatic beta cell death through degradation of JUNB and inhibition of the unfolded protein response, leading to reduction of insulin secretion (PubMed:26319551). Restricts the production of proinflammatory cytokines in effector Th17 T-cells by promoting ITCH-mediated ubiquitination and degradation of RORC (PubMed:28051111). Together with NDFIP2, limits the cytokine signaling and expansion of effector Th2 T-cells by promoting degradation of JAK1, probably by ITCH- and NEDD4L-mediated ubiquitination (PubMed:27088444). Regulates peripheral T-cell tolerance to self and foreign antigens, forcing the exit of naive CD4+ T-cells from the cell cycle before they become effector T-cells (PubMed:24520172, PubMed:28051111). Negatively regulates RLR-mediated antiviral response by promoting SMURF1-mediated ubiquitination and subsequent degradation of MAVS (By similarity). Negatively regulates KCNH2 potassium channel activity by decreasing its cell-surface expression and interfering with channel maturation through recruitment of NEDD4L to the Golgi apparatus where it mediates KCNH2 degradation (By similarity). In cortical neurons, mediates the ubiquitination of the divalent metal transporter SLC11A2/DMT1 by NEDD4L, leading to its down-regulation and protection of the cells from cobalt and iron toxicity (By similarity). Important for normal development of dendrites and dendritic spines in cortex (PubMed:23897647). Enhances the ubiquitination of BRAT1 mediated by: NEDD4, NEDD4L and ITCH and is required for the nuclear localization of ubiquitinated BRAT1 (PubMed:25631046). Enhances the ITCH-mediated ubiquitination of MAP3K7 by recruiting E2 ubiquitin-conjugating enzyme UBE2L3 to ITCH (PubMed:25632008). Modulates EGFR signaling through multiple pathways. In particular, may regulate the ratio of AKT1-to-MAPK8 signaling in response to EGF, acting on AKT1 probably through PTEN destabilization and on MAPK8 through ITCH-dependent MAP2K4 inactivation. As a result, may control cell growth rate (By similarity). Inhibits cell proliferation by promoting PTEN nuclear localization and changing its signaling specificity (PubMed:25801959).By similarity11 Publications

GO - Molecular functioni

  • WW domain binding Source: GO_Central

GO - Biological processi

Names & Taxonomyi

Protein namesi
Recommended name:
NEDD4 family-interacting protein 1
Alternative name(s):
NEDD4 WW domain-binding protein 5
Gene namesi
Name:Ndfip1
Synonyms:N4wbp5
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 18

Organism-specific databases

MGIiMGI:1929601 Ndfip1

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini2 – 116CytoplasmicSequence analysisAdd BLAST115
Transmembranei117 – 137HelicalSequence analysisAdd BLAST21
Topological domaini138 – 143ExtracellularSequence analysis6
Transmembranei144 – 164HelicalSequence analysisAdd BLAST21
Topological domaini165 – 172CytoplasmicSequence analysis8
Transmembranei173 – 193HelicalSequence analysisAdd BLAST21
Topological domaini194 – 221ExtracellularSequence analysisAdd BLAST28

Keywords - Cellular componenti

Cell junction, Cell projection, Endosome, Golgi apparatus, Membrane, Secreted, Synapse, Synaptosome

Pathology & Biotechi

Disruption phenotypei

Mutant mice appear normal at birth, but develop severe skin and gastrointestinal tract inflammation around 6 to 8 weeks of age (PubMed:17137798, PubMed:20962770). They do not survive beyond 14 weeks (PubMed:17137798). This phenotype is due to the lack of activity of ITCH E3 ubiquitin-protein ligase, and consequently, prolongation of JUNB half-life after T-cell activation (PubMed:17137798, PubMed:20962770). This results in an increased production of T-helper 2 (Th2) cytokines and in the promotion of Th2-mediated inflammation (PubMed:17137798, PubMed:20962770). This subsequently leads to increased number of circulating, esophagus and small bowel eosinophils (PubMed:20962770). Mutant mice have thicker small bowel and do not gain as much weight as the wild type (PubMed:20962770). Mutant mice also show an increased iron transport in hepatocytes and iron accumulation in the liver around portal veins, in the villi of duodenum and throughout the brain cortex (PubMed:18776082, PubMed:19706893).4 Publications

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi42Y → A: Abolishes interaction with NEDD4. 1 Publication1
Mutagenesisi67Y → A: Alters interaction with NEDD4. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedBy similarity
ChainiPRO_00000762702 – 221NEDD4 family-interacting protein 1Add BLAST220

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylalanineBy similarity1

Post-translational modificationi

Ubiquitinated by NEDD4; mono-, di- and polyubiquitinated forms are detected. Ubiquitination regulates its degradation.1 Publication
Undergoes transient tyrosine phosphorylation following EGF stimulation, most probably by catalyzed by SRC. Phosphorylation SRC is enhanced in the presence of NDFIP2 which may act as a scaffold to recruit SRC to NDFIP1 (By similarity).By similarity

Keywords - PTMi

Acetylation, Ubl conjugation

Proteomic databases

MaxQBiQ8R0W6
PaxDbiQ8R0W6
PeptideAtlasiQ8R0W6
PRIDEiQ8R0W6

PTM databases

iPTMnetiQ8R0W6
PhosphoSitePlusiQ8R0W6
SwissPalmiQ8R0W6

Expressioni

Tissue specificityi

Highly expressed in embryonic and early postnatal cortex (at protein level) (PubMed:23897647). Widely expressed (PubMed:11748237). Hardly detectable in resting T-cells; up-regulated in T-cells in response to activation (PubMed:17137798).3 Publications

Inductioni

Up-regulated after traumatic brain injury in surviving neurons around the lesion site.1 Publication

Gene expression databases

BgeeiENSMUSG00000024425 Expressed in 275 organ(s), highest expression level in pineal body
CleanExiMM_NDFIP1
GenevisibleiQ8R0W6 MM

Interactioni

Subunit structurei

Forms heterodimers with NDFIP2 (By similarity). Interacts with several E3 ubiquitin-protein ligases, including ITCH, NEDD4, NEDD4L and WWP2 (PubMed:11042109, PubMed:11748237, PubMed:17137798, PubMed:25632008). The interaction with NEDD4, NEDD4L and ITCH leads to relocalization of these proteins to exosomes and eventually to exosomal secretion (PubMed:11748237). Interacts with U2SURP (PubMed:11748237). Interacts with SLC11A2/DMT1 (By similarity). Interacts with PTEN (By similarity). May interact with phosphorylated EGFR (By similarity). Interacts with BRAT1 (By similarity). Interacts with KCNH2 (By similarity). Interacts with MAVS (By similarity). Part of a complex containing ITCH, NDFIP1 and MAP3K7 (PubMed:25632008). Interacts (via N-terminus) with UBE2L3; the interaction mediates recruitment of UBE2L3 to ITCH (PubMed:25632008).By similarity4 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
Nedd4P469355EBI-6304119,EBI-773516

GO - Molecular functioni

Protein-protein interaction databases

BioGridi211136, 11 interactors
IntActiQ8R0W6, 1 interactor
STRINGi10090.ENSMUSP00000025293

Structurei

3D structure databases

ProteinModelPortaliQ8R0W6
SMRiQ8R0W6
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni2 – 41Interaction with UBE2L31 PublicationAdd BLAST40
Regioni42 – 76Interaction with ITCH1 PublicationAdd BLAST35

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi39 – 42PPxY motif 14
Motifi64 – 67PPxY motif 24
Motifi74 – 76PPxY motif 33

Domaini

The PPxY motifs are required for E3 ubiquitin-protein ligase binding and activation and for ubiquitination.2 Publications

Keywords - Domaini

Repeat, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG4812 Eukaryota
ENOG4111M6U LUCA
GeneTreeiENSGT00390000012721
HOGENOMiHOG000038752
HOVERGENiHBG057103
InParanoidiQ8R0W6
OMAiIPMQMQV
OrthoDBiEOG091G0IMV
PhylomeDBiQ8R0W6
TreeFamiTF324911

Family and domain databases

InterProiView protein in InterPro
IPR019325 NEDD4/Bsd2
PANTHERiPTHR13396 PTHR13396, 1 hit
PfamiView protein in Pfam
PF10176 DUF2370, 1 hit

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

Q8R0W6-1 [UniParc]FASTAAdd to basket
« Hide
        10         20         30         40         50
MALALAALAA VEPACGSGYQ QLQNEEEPGE PEQTAGDAPP PYSSITAESA
60 70 80 90 100
AYFDYKDESG FPKPPSYNVA TTLPSYDEAE RTKTEATIPL VPGRDEDFVG
110 120 130 140 150
RDDFDDTDQL RIGNDGIFML TFFMAFLFNW IGFFLSFCLT TSAAGRYGAI
160 170 180 190 200
SGFGLSLIKW ILIVRFSTYF PGYFDGQYWL WWVFLVLGFL LFLRGFINYA
210 220
KVRKMPETFS NLPRTRVLFI Y
Length:221
Mass (Da):24,914
Last modified:June 1, 2002 - v1
Checksum:i7699A062161AC6A4
GO

Sequence cautioni

The sequence AAG44248 differs from that shown. Reason: Erroneous initiation.Curated

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF220209 mRNA Translation: AAG44248.1 Different initiation.
AK050560 mRNA Translation: BAC34324.1
BC026372 mRNA Translation: AAH26372.1
CCDSiCCDS37789.1
RefSeqiNP_075372.1, NM_022996.1
XP_006526212.1, XM_006526149.1
UniGeneiMm.102496

Genome annotation databases

EnsembliENSMUST00000025293; ENSMUSP00000025293; ENSMUSG00000024425
GeneIDi65113
KEGGimmu:65113
UCSCiuc008esj.1 mouse

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF220209 mRNA Translation: AAG44248.1 Different initiation.
AK050560 mRNA Translation: BAC34324.1
BC026372 mRNA Translation: AAH26372.1
CCDSiCCDS37789.1
RefSeqiNP_075372.1, NM_022996.1
XP_006526212.1, XM_006526149.1
UniGeneiMm.102496

3D structure databases

ProteinModelPortaliQ8R0W6
SMRiQ8R0W6
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi211136, 11 interactors
IntActiQ8R0W6, 1 interactor
STRINGi10090.ENSMUSP00000025293

PTM databases

iPTMnetiQ8R0W6
PhosphoSitePlusiQ8R0W6
SwissPalmiQ8R0W6

Proteomic databases

MaxQBiQ8R0W6
PaxDbiQ8R0W6
PeptideAtlasiQ8R0W6
PRIDEiQ8R0W6

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000025293; ENSMUSP00000025293; ENSMUSG00000024425
GeneIDi65113
KEGGimmu:65113
UCSCiuc008esj.1 mouse

Organism-specific databases

CTDi80762
MGIiMGI:1929601 Ndfip1

Phylogenomic databases

eggNOGiKOG4812 Eukaryota
ENOG4111M6U LUCA
GeneTreeiENSGT00390000012721
HOGENOMiHOG000038752
HOVERGENiHBG057103
InParanoidiQ8R0W6
OMAiIPMQMQV
OrthoDBiEOG091G0IMV
PhylomeDBiQ8R0W6
TreeFamiTF324911

Miscellaneous databases

PROiPR:Q8R0W6
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000024425 Expressed in 275 organ(s), highest expression level in pineal body
CleanExiMM_NDFIP1
GenevisibleiQ8R0W6 MM

Family and domain databases

InterProiView protein in InterPro
IPR019325 NEDD4/Bsd2
PANTHERiPTHR13396 PTHR13396, 1 hit
PfamiView protein in Pfam
PF10176 DUF2370, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiNFIP1_MOUSE
AccessioniPrimary (citable) accession number: Q8R0W6
Secondary accession number(s): Q9EQH8
Entry historyiIntegrated into UniProtKB/Swiss-Prot: December 6, 2005
Last sequence update: June 1, 2002
Last modified: November 7, 2018
This is version 119 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health

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