Q9BT67 (NFIP1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	221 AA.
Sequence status	Complete.
Protein existence	Evidence 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 component	Endosome Golgi apparatus Membrane Secreted
Coding sequence diversity	Alternative splicing
Domain	Repeat Transmembrane Transmembrane helix
PTM	Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	cellular iron ion homeostasis Inferred from mutant phenotype Ref.9. Source: UniProtKB negative regulation of T cell proliferation Inferred from electronic annotation. Source: Compara negative regulation of gene expression Inferred from mutant phenotype Ref.9. Source: UniProtKB negative regulation of inflammatory response Inferred from electronic annotation. Source: Compara negative regulation of interleukin-4 production Inferred from electronic annotation. Source: Compara negative regulation of isotype switching to IgE isotypes Inferred from electronic annotation. Source: Compara 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: Compara positive regulation of I-kappaB kinase/NF-kappaB cascade Inferred from mutant phenotype Ref.2. Source: UniProtKB positive regulation of protein catabolic process Inferred from electronic annotation. Source: Compara 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: Compara regulation of lymphocyte differentiation Inferred from electronic annotation. Source: Compara regulation of myeloid leukocyte differentiation Inferred from electronic annotation. Source: Compara ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway Inferred from electronic annotation. Source: Compara
Cellular_component	Golgi membrane Inferred from electronic annotation. Source: UniProtKB-SubCell cell cortex Inferred from electronic annotation. Source: Compara endosome membrane Inferred from electronic annotation. Source: UniProtKB-SubCell extracellular region Inferred from electronic annotation. Source: UniProtKB-SubCell integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW perinuclear region of cytoplasm Inferred from direct assay Ref.9. Source: UniProtKB
Molecular_function	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 key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 221	221	NEDD4 family-interacting protein 1		PRO_0000076269
Regions
	Topological domain	1 – 116	116	Cytoplasmic Potential
	Transmembrane	117 – 137	21	Helical; Potential
	Topological domain	138 – 143	6	Extracellular Potential
	Transmembrane	144 – 164	21	Helical; Potential
	Topological domain	165 – 172	8	Cytoplasmic Potential
	Transmembrane	173 – 193	21	Helical; Potential
	Topological domain	194 – 221	28	Extracellular Potential
	Motif	40 – 42	3	PY 1
	Motif	65 – 67	3	PY 2
	Motif	74 – 76	3	PY 3
Natural variations
	Alternative sequence	76 – 153	78	YDEAE…AISGF → CFYDISHLIFFIFYLRNMKK KYTKMVKLLHKSAPAQSDSC KCPFICCVCISRISIGSRSG YQYIMHRSVGCLKAKQEN in isoform 2.		VSP_016474
	Alternative sequence	154 – 221	68	Missing in isoform 2.		VSP_016475
Experimental info
	Mutagenesis	41 – 42	2	PY → 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
	Mutagenesis	66 – 67	2	SY → 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
	Mutagenesis	75 – 76	2	SY → 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 conflict	20	1	Q → W in BAC11670. Ref.4
	Sequence conflict	104	1	F → L in BAC11670. Ref.4

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified June 1, 2001. Version 1. Checksum: 526A579D7B32FCA4	FASTA	221	24,899
	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
	Isoform 2 [UniParc]. Checksum: D8A2706965DD8A23	FASTA	153	16,915
	10 20 30 40 50 60 MALALAALAA VEPACGSRYQ QLQNEEESGE PEQAAGDAPP PYSSISAESA AYFDYKDESG 70 80 90 100 110 120 FPKPPSYNVA TTLPSCFYDI SHLIFFIFYL RNMKKKYTKM VKLLHKSAPA QSDSCKCPFI 130 140 150 CCVCISRISI GSRSGYQYIM HRSVGCLKAK QEN

References

	« Hide 'large scale' referencesShow '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. , 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. , 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. , 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.
+	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.
IPI	IPI00012235. IPI00179987.
RefSeq	NP_085048.1. NM_030571.3.
UniGene	Hs.653510. Hs.9788.
3D structure databases
ProteinModelPortal	Q9BT67.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP-48958N.
STRING	9606.ENSP00000253814.
PTM databases
PhosphoSite	Q9BT67.
Polymorphism databases
DMDM	74733098.
Proteomic databases
PaxDb	Q9BT67.
PRIDE	Q9BT67.
Protocols and materials databases
DNASU	80762.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000253814; ENSP00000253814; ENSG00000131507.
GeneID	80762.
KEGG	hsa:80762.
UCSC	uc003lmi.4. human.
Organism-specific databases
CTD	80762.
GeneCards	GC05P141468.
HGNC	HGNC:17592. NDFIP1.
HPA	HPA009682.
MIM	612050. gene.
neXtProt	NX_Q9BT67.
PharmGKB	PA134943402.
GenAtlas	Search...
Phylogenomic databases
eggNOG	NOG311167.
HOGENOM	HOG000038752.
HOVERGEN	HBG057103.
InParanoid	Q9BT67.
OMA	TAYFDYK.
OrthoDB	EOG47D9H7.
PhylomeDB	Q9BT67.
Gene expression databases
Bgee	Q9BT67.
CleanEx	HS_NDFIP1.
Genevestigator	Q9BT67.
GermOnline	ENSG00000131507. Homo sapiens.
Family and domain databases
InterPro	IPR019325. NEDD4/BSD2. [Graphical view]
Pfam	PF10176. DUF2370. 2 hits. [Graphical view]
ProtoNet	Search...
Other
ChiTaRS	NDFIP1. human.
GenomeRNAi	80762.
NextBio	71137.
SOURCE	Search...

Entry information

Entry name

NFIP1_HUMAN

Accession

Primary (citable) accession number: Q9BT67
Secondary accession number(s): B2RDB8 , D3DQF0, Q658T8, Q8N2E3, Q8N2F9

Entry history

Integrated into UniProtKB/Swiss-Prot:	December 6, 2005
Last sequence update:	June 1, 2001
Last modified:	April 3, 2013
This is version 80 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.