Skip Header

You are using a version of Internet Explorer that may not display all features of this website. Please upgrade to a modern browser.
Contribute Send feedback
Read comments (?) or add your own

Q9BT67 (NFIP1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 90. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (2) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
NEDD4 family-interacting protein 1
Alternative name(s):
Breast cancer-associated protein SGA-1M
NEDD4 WW domain-binding protein 5
Putative MAPK-activating protein PM13
Putative NF-kappa-B-activating protein 164
Putative NFKB and MAPK-activating protein
Gene names
Name:NDFIP1
Synonyms:N4WBP5
ORF Names:PSEC0192, PSEC0223
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length221 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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 cells-mediated inflammation by activating ITCH and thus controlling JUNB degradation By similarity. In cortical neurons, mediates the ubiquitination of SLC11A2/DMT1 by NEDD4L, leading to down-regulation of the divalent metal transporter and protection of the cells from cobalt and iron toxicity. 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. Ref.11 Ref.12 Ref.13

Subunit structure

Forms heterodimers with NDFIP2. Interacts with several E3 ubiquitin-protein ligases, including NEDD4, NEDD4L and WWP2. Interacts with ITCH, U2SURP and WWP2 By similarity. The interaction with NEDD4, NEDD4L and ITCH leads to relocalization of these proteins to exosomes and eventually to exosomal secretion. Interacts with SLC11A2/DMT1. Interacts with PTEN. May interact with phosphorylated EGFR. Ref.9 Ref.12 Ref.13

Subcellular location

Endosome membrane; Multi-pass membrane protein. Golgi apparatus membrane By similarity. Secreted. Note: Detected in exosomes and secreted via the exosomal pathway. Ref.9 Ref.10 Ref.13

Tissue specificity

Widely expressed. Higher levels are detected in cerebellum, pituitary, thalamus, kidney, liver, testis, salivary glands and placenta. Also expressed in fetal brain, kidney and lung. Ref.8

Induction

Increased protein expression in neuronal cells in response to Co2+ or Fe2+ ions. Ref.12

Domain

The PY (WW-binding) motifs are required for E3 ubiquitin-protein ligase binding and activation and for ubiquitination.

Post-translational modification

Ubiquitinated by NEDD4 and ITCH; mono-, di- and polyubiquitinated forms are detected. Ubiquitination regulates its degradation. Ref.11

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.

Ontologies

Keywords
   Cellular componentEndosome
Golgi apparatus
Membrane
Secreted
   Coding sequence diversityAlternative splicing
   DomainRepeat
Transmembrane
Transmembrane helix
   PTMAcetylation
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processcellular iron ion homeostasis

Inferred from mutant phenotype Ref.9. Source: UniProtKB

negative regulation of T cell proliferation

Inferred from electronic annotation. Source: Ensembl

negative regulation of gene expression

Inferred from mutant phenotype Ref.9. Source: UniProtKB

negative regulation of inflammatory response

Inferred from electronic annotation. Source: Ensembl

negative regulation of interleukin-4 production

Inferred from electronic annotation. Source: Ensembl

negative regulation of isotype switching to IgE isotypes

Inferred from electronic annotation. Source: Ensembl

negative regulation of protein transport

Inferred from mutant phenotype Ref.9. Source: UniProtKB

negative regulation of transporter activity

Inferred from mutant phenotype Ref.9. Source: UniProtKB

negative regulation of type 2 immune response

Inferred from electronic annotation. Source: Ensembl

positive regulation of I-kappaB kinase/NF-kappaB signaling

Inferred from mutant phenotype Ref.2. Source: UniProtKB

positive regulation of protein catabolic process

Inferred from electronic annotation. Source: Ensembl

positive regulation of protein ubiquitination

Inferred from mutant phenotype Ref.9. Source: UniProtKB

regulation of isotype switching to IgG isotypes

Inferred from electronic annotation. Source: Ensembl

regulation of lymphocyte differentiation

Inferred from electronic annotation. Source: Ensembl

regulation of myeloid leukocyte differentiation

Inferred from electronic annotation. Source: Ensembl

signal transduction

Inferred from mutant phenotype Ref.2. Source: GOC

ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway

Inferred from electronic annotation. Source: Ensembl

   Cellular_componentGolgi membrane

Inferred from electronic annotation. Source: UniProtKB-SubCell

cell cortex

Inferred from electronic annotation. Source: Ensembl

endosome membrane

Inferred from electronic annotation. Source: UniProtKB-SubCell

extracellular region

Inferred from electronic annotation. Source: UniProtKB-SubCell

integral component of membrane

Inferred from electronic annotation. Source: UniProtKB-KW

perinuclear region of cytoplasm

Inferred from direct assay Ref.9. Source: UniProtKB

   Molecular_functionprotein binding

Inferred from physical interaction Ref.9. Source: UniProtKB

signal transducer activity

Inferred from mutant phenotype Ref.2. Source: UniProtKB

Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: Q9BT67-1)

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.
Isoform 2 (identifier: Q9BT67-2)

The sequence of this isoform differs from the canonical sequence as follows:
     76-153: YDEAERTKAE...AGRYGAISGF → CFYDISHLIF...VGCLKAKQEN
     154-221: Missing.
Note: No experimental confirmation available.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Initiator methionine11Removed Ref.14
Chain2 – 221220NEDD4 family-interacting protein 1
PRO_0000076269

Regions

Topological domain2 – 116115Cytoplasmic Potential
Transmembrane117 – 13721Helical; Potential
Topological domain138 – 1436Extracellular Potential
Transmembrane144 – 16421Helical; Potential
Topological domain165 – 1728Cytoplasmic Potential
Transmembrane173 – 19321Helical; Potential
Topological domain194 – 22128Extracellular Potential
Motif40 – 423PY 1
Motif65 – 673PY 2
Motif74 – 763PY 3

Amino acid modifications

Modified residue21N-acetylalanine Ref.14

Natural variations

Alternative sequence76 – 15378YDEAE…AISGF → CFYDISHLIFFIFYLRNMKK KYTKMVKLLHKSAPAQSDSC KCPFICCVCISRISIGSRSG YQYIMHRSVGCLKAKQEN in isoform 2.
VSP_016474
Alternative sequence154 – 22168Missing in isoform 2.
VSP_016475

Experimental info

Mutagenesis41 – 422PY → AG: Loss of phosphorylation; when associated with 66-S-Y-67 and 75-S-Y-76. Greatly decreases NEDD4-binding; when associated with 66-S-Y-67 and 75-S-Y-76. No effect on PTEN-binding; when associated with 66-S-Y-67 and 75-S-Y-76. Ref.13
Mutagenesis66 – 672SY → AG: Loss of phosphorylation; when associated with 41-P-Y-42 and 75-S-Y-76. Greatly decreases NEDD4-binding; when associated with 41-P-Y-42 and 75-S-Y-76. No effect on PTEN-binding; when associated with 41-P-Y-42 and 75-S-Y-76. Ref.13
Mutagenesis75 – 762SY → AG: Loss of phosphorylation; when associated with 41-P-Y-42 and 66-S-Y-67. Greatly decreases NEDD4-binding; when associated with 41-P-Y-42 and 66-S-Y-67. No effect on PTEN-binding; when associated with 41-P-Y-42 and 66-S-Y-67. Ref.13
Sequence conflict201Q → W in BAC11670. Ref.4
Sequence conflict1041F → L in BAC11670. Ref.4

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified June 1, 2001. Version 1.
Checksum: 526A579D7B32FCA4

FASTA22124,899
        10         20         30         40         50         60 
MALALAALAA VEPACGSRYQ QLQNEEESGE PEQAAGDAPP PYSSISAESA AYFDYKDESG 

        70         80         90        100        110        120 
FPKPPSYNVA TTLPSYDEAE RTKAEATIPL VPGRDEDFVG RDDFDDADQL RIGNDGIFML 

       130        140        150        160        170        180 
TFFMAFLFNW IGFFLSFCLT TSAAGRYGAI SGFGLSLIKW ILIVRFSTYF PGYFDGQYWL 

       190        200        210        220 
WWVFLVLGFL LFLRGFINYA KVRKMPETFS NLPRTRVLFI Y 

« Hide

Isoform 2 [UniParc].

Checksum: D8A2706965DD8A23
Show »

FASTA15316,915

References

« Hide 'large scale' references
[1]"Array analysis of subtractive cDNA libraries identifies SGA-1M: a novel breast cancer-associated gene."
Petroziello J.M., Westendorf L.E., Gordon K.A., Yamane A.K., Cerveny C.G., Wahl A.F., Law C.L.
Submitted (DEC-2002) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[2]"Large-scale identification and characterization of human genes that activate NF-kappaB and MAPK signaling pathways."
Matsuda A., Suzuki Y., Honda G., Muramatsu S., Matsuzaki O., Nagano Y., Doi T., Shimotohno K., Harada T., Nishida E., Hayashi H., Sugano S.
Oncogene 22:3307-3318(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
Tissue: Lung fibroblast.
[3]"Complete sequencing and characterization of 21,243 full-length human cDNAs."
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. expand/collapse author list , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
Tissue: Embryo.
[4]"Signal sequence and keyword trap in silico for selection of full-length human cDNAs encoding secretion or membrane proteins from oligo-capped cDNA libraries."
Otsuki T., Ota T., Nishikawa T., Hayashi K., Suzuki Y., Yamamoto J., Wakamatsu A., Kimura K., Sakamoto K., Hatano N., Kawai Y., Ishii S., Saito K., Kojima S., Sugiyama T., Ono T., Okano K., Yoshikawa Y. expand/collapse author list , Aotsuka S., Sasaki N., Hattori A., Okumura K., Nagai K., Sugano S., Isogai T.
DNA Res. 12:117-126(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
Tissue: Embryo.
[5]Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases
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] (ISOFORM 1).
Tissue: Brain.
[7]"The full-ORF clone resource of the German cDNA consortium."
Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., Wiemann S., Schupp I.
BMC Genomics 8:399-399(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 102-221 (ISOFORM 1).
Tissue: Stomach.
[8]"N4WBP5, a potential target for ubiquitination by the Nedd4 family of proteins, is a novel Golgi-associated protein."
Harvey K.F., Shearwin-Whyatt L.M., Fotia A., Parton R.G., Kumar S.
J. Biol. Chem. 277:9307-9317(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: TISSUE SPECIFICITY.
[9]"Regulation of the divalent metal ion transporter DMT1 and iron homeostasis by a ubiquitin-dependent mechanism involving Ndfips and WWP2."
Foot N.J., Dalton H.E., Shearwin-Whyatt L.M., Dorstyn L., Tan S.S., Yang B., Kumar S.
Blood 112:4268-4275(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION, INTERACTION WITH SLC11A2 AND WWP2.
[10]"Nedd4 family-interacting protein 1 (Ndfip1) is required for the exosomal secretion of Nedd4 family proteins."
Putz U., Howitt J., Lackovic J., Foot N., Kumar S., Silke J., Tan S.S.
J. Biol. Chem. 283:32621-32627(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION.
[11]"Control of the activity of WW-HECT domain E3 ubiquitin ligases by NDFIP proteins."
Mund T., Pelham H.R.
EMBO Rep. 10:501-507(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, UBIQUITINATION.
[12]"Divalent metal transporter 1 (DMT1) regulation by Ndfip1 prevents metal toxicity in human neurons."
Howitt J., Putz U., Lackovic J., Doan A., Dorstyn L., Cheng H., Yang B., Chan-Ling T., Silke J., Kumar S., Tan S.S.
Proc. Natl. Acad. Sci. U.S.A. 106:15489-15494(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH SLC11A2 AND NEDD4L, INDUCTION BY COBALT AND IRON.
[13]"Regulation of PTEN/Akt and MAP kinase signaling pathways by the ubiquitin ligase activators Ndfip1 and Ndfip2."
Mund T., Pelham H.R.
Proc. Natl. Acad. Sci. U.S.A. 107:11429-11434(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH NDFIP2; NEDD4 AND PTEN, SUBCELLULAR LOCATION, PHOSPHORYLATION, MUTAGENESIS OF 41-PRO-TYR-42; 66-SER-TYR-67 AND 75-SER-TYR-76.
[14]"Comparative large-scale characterisation of plant vs. mammal proteins reveals similar and idiosyncratic N-alpha acetylation features."
Bienvenut W.V., Sumpton D., Martinez A., Lilla S., Espagne C., Meinnel T., Giglione C.
Mol. Cell. Proteomics 11:M111.015131-M111.015131(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS], CLEAVAGE OF INITIATOR METHIONINE [LARGE SCALE ANALYSIS].
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AY192728 mRNA. Translation: AAP13460.1.
AB097010 mRNA. Translation: BAC77363.1.
AB097037 mRNA. Translation: BAC77390.1.
AK075495 mRNA. Translation: BAC11652.1.
AK075524 mRNA. Translation: BAC11670.1.
AK315481 mRNA. Translation: BAG37865.1.
CH471062 Genomic DNA. Translation: EAW61888.1.
CH471062 Genomic DNA. Translation: EAW61889.1.
BC004317 mRNA. Translation: AAH04317.1.
AL832993 mRNA. Translation: CAH56294.1.
CCDSCCDS4273.1. [Q9BT67-1]
RefSeqNP_085048.1. NM_030571.3. [Q9BT67-1]
UniGeneHs.653510.
Hs.9788.

3D structure databases

ProteinModelPortalQ9BT67.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid123296. 7 interactions.
DIPDIP-48958N.
STRING9606.ENSP00000253814.

PTM databases

PhosphoSiteQ9BT67.

Polymorphism databases

DMDM74733098.

Proteomic databases

MaxQBQ9BT67.
PaxDbQ9BT67.
PRIDEQ9BT67.

Protocols and materials databases

DNASU80762.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000253814; ENSP00000253814; ENSG00000131507. [Q9BT67-1]
GeneID80762.
KEGGhsa:80762.
UCSCuc003lmi.4. human. [Q9BT67-1]

Organism-specific databases

CTD80762.
GeneCardsGC05P141468.
HGNCHGNC:17592. NDFIP1.
HPAHPA009682.
MIM612050. gene.
neXtProtNX_Q9BT67.
PharmGKBPA134943402.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG311167.
HOGENOMHOG000038752.
HOVERGENHBG057103.
InParanoidQ9BT67.
OMATAYFDYK.
OrthoDBEOG7Z69DP.
PhylomeDBQ9BT67.
TreeFamTF324911.

Gene expression databases

BgeeQ9BT67.
CleanExHS_NDFIP1.
GenevestigatorQ9BT67.

Family and domain databases

InterProIPR019325. NEDD4/BSD2.
[Graphical view]
PfamPF10176. DUF2370. 2 hits.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSNDFIP1. human.
GenomeRNAi80762.
NextBio71137.
PROQ9BT67.
SOURCESearch...

Entry information

Entry nameNFIP1_HUMAN
AccessionPrimary (citable) accession number: Q9BT67
Secondary accession number(s): B2RDB8 expand/collapse secondary AC list , D3DQF0, Q658T8, Q8N2E3, Q8N2F9
Entry history
Integrated into UniProtKB/Swiss-Prot: December 6, 2005
Last sequence update: June 1, 2001
Last modified: July 9, 2014
This is version 90 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human chromosome 5

Human chromosome 5: entries, gene names and cross-references to MIM