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Q9C004 (SPY4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 110. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Protein sprouty homolog 4

Short name=Spry-4
Gene names
Name:SPRY4
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length299 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Suppresses the insulin receptor and EGFR-transduced MAPK signaling pathway, but does not inhibit MAPK activation by a constitutively active mutant Ras. Probably impairs the formation of GTP-Ras. Inhibits Ras-independent, but not Ras-dependent, activation of RAF1. Ref.6

Subunit structure

Interacts with the C-terminus of TESK1. Interacts with RAF1. Ref.1 Ref.6

Subcellular location

Cytoplasm. Cell projectionruffle membrane; Peripheral membrane protein; Cytoplasmic side Potential Ref.1.

Domain

The Cys-rich domain is responsible for the localization of the protein to the membrane ruffles.

Involvement in disease

Hypogonadotropic hypogonadism 17 with or without anosmia (HH17) [MIM:615266]: A disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. In some cases, it is associated with non-reproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss. Anosmia or hyposmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to deficiency in gonadotropin-releasing hormone and probably results from a failure of embryonic migration of gonadotropin-releasing hormone-synthesizing neurons. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism is referred to as Kallmann syndrome, whereas in the presence of a normal sense of smell, it has been termed normosmic idiopathic hypogonadotropic hypogonadism (nIHH).
Note: The disease is caused by mutations affecting distinct genetic loci, including the gene represented in this entry. Some patients carrying mutations in SPRY4 also have a heterozygous mutation in another HH-associated gene including DUSP6 and FGFR1 (Ref.10). Ref.10

Sequence similarities

Belongs to the sprouty family.

Contains 1 SPR (sprouty) domain.

Sequence caution

The sequence AAK00652.1 differs from that shown. Reason: Erroneous initiation.

Binary interactions

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform A (identifier: Q9C004-1)

Also known as: Sprouty-4A;

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 C (identifier: Q9C004-2)

Also known as: Sprouty-4C;

The sequence of this isoform differs from the canonical sequence as follows:
     97-106: SSVSSSSSTS → CSATCLPPAA
     107-299: Missing.
Note: No experimental confirmation available.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 299299Protein sprouty homolog 4
PRO_0000076905

Regions

Domain166 – 273108SPR
Compositional bias97 – 10711Poly-Ser
Compositional bias159 – 283125Cys-rich

Amino acid modifications

Modified residue11N-acetylmethionine Ref.9
Modified residue1251Phosphoserine Ref.8

Natural variations

Alternative sequence97 – 10610SSVSSSSSTS → CSATCLPPAA in isoform C.
VSP_006219
Alternative sequence107 – 299193Missing in isoform C.
VSP_006220
Natural variant771T → M in HH17; phenotype consistent with Kallmann syndrome. Ref.10
VAR_069929
Natural variant821D → N in HH17; without anosmia. Ref.10
VAR_069930
Natural variant1541K → R in HH17; phenotype consistent with Kallmann syndrome. Ref.10
Corresponds to variant rs78310959 [ dbSNP | Ensembl ].
VAR_069931
Natural variant1861C → Y in HH17; phenotype consistent with Kallmann syndrome. Ref.10
Corresponds to variant rs148983803 [ dbSNP | Ensembl ].
VAR_069932
Natural variant2181S → Y in HH17; rare variant associated with susceptibility to disease; some patients have a second mutation in another HH-associated gene including DUSP6 and FGFR1. Ref.10
Corresponds to variant rs139512218 [ dbSNP | Ensembl ].
VAR_069933
Natural variant2581V → M in HH17; without anosmia. Ref.10
Corresponds to variant rs200364529 [ dbSNP | Ensembl ].
VAR_069934
Natural variant2811V → I in HH17; without anosmia. Ref.10
Corresponds to variant rs142439525 [ dbSNP | Ensembl ].
VAR_069935

Experimental info

Sequence conflict1021S → N in AAI25097. Ref.5

Sequences

Sequence LengthMass (Da)Tools
Isoform A (Sprouty-4A) [UniParc].

Last modified July 11, 2001. Version 2.
Checksum: 105F6F1BE9F7B6C3

FASTA29932,541
        10         20         30         40         50         60 
MEPPIPQSAP LTPNSVMVQP LLDSRMSHSR LQHPLTILPI DQVKTSHVEN DYIDNPSLAL 

        70         80         90        100        110        120 
TTGPKRTRGG APELAPTPAR CDQDVTHHWI SFSGRPSSVS SSSSTSSDQR LLDHMAPPPV 

       130        140        150        160        170        180 
ADQASPRAVR IQPKVVHCQP LDLKGPAVPP ELDKHFLLCE ACGKCKCKEC ASPRTLPSCW 

       190        200        210        220        230        240 
VCNQECLCSA QTLVNYGTCM CLVQGIFYHC TNEDDEGSCA DHPCSCSRSN CCARWSFMGA 

       250        260        270        280        290 
LSVVLPCLLC YLPATGCVKL AQRGYDRLRR PGCRCKHTNS VICKAASGDA KTSRPDKPF 

« Hide

Isoform C (Sprouty-4C) [UniParc].

Checksum: 6158571E3477A598
Show »

FASTA10611,482

References

« Hide 'large scale' references
[1]"Human sprouty 4, a new ras antagonist on 5q31, interacts with the dual specificity kinase TESK1."
Leeksma O.C., van Achterberg T.A.E., Tsumura Y., Toshima J., Eldering E., Kroes W.G.M., Mellink C., Spaargaren M., Mizuno K., Pannekoek H., de Vries C.J.M.
Eur. J. Biochem. 269:2546-2556(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS A AND C), CHARACTERIZATION, SUBCELLULAR LOCATION, INTERACTION WITH TESK1.
Tissue: Umbilical artery.
[2]"Genomic structure and promoter characterization of the human Sprouty4 gene, a novel regulator of lung morphogenesis."
Ding W., Bellusci S., Shi W., Warburton D.
Am. J. Physiol. 287:L52-L59(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[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] (ISOFORM A).
Tissue: Brain.
[4]"The DNA sequence and comparative analysis of human chromosome 5."
Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S., Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M., She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S. expand/collapse author list , Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M., Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M.
Nature 431:268-274(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]"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 A).
[6]"Mammalian Sprouty4 suppresses Ras-independent ERK activation by binding to Raf1."
Sasaki A., Taketomi T., Kato R., Saeki K., Nonami A., Sasaki M., Kuriyama M., Saito N., Shibuya M., Yoshimura A.
Nat. Cell Biol. 5:427-432(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH RAF1.
[7]"A quantitative atlas of mitotic phosphorylation."
Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P.
Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[8]"System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation."
Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.
Sci. Signal. 4:RS3-RS3(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-125, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[9]"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 MET-1, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[10]"Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism."
Miraoui H., Dwyer A.A., Sykiotis G.P., Plummer L., Chung W., Feng B., Beenken A., Clarke J., Pers T.H., Dworzynski P., Keefe K., Niedziela M., Raivio T., Crowley W.F. Jr., Seminara S.B., Quinton R., Hughes V.A., Kumanov P. expand/collapse author list , Young J., Yialamas M.A., Hall J.E., Van Vliet G., Chanoine J.P., Rubenstein J., Mohammadi M., Tsai P.S., Sidis Y., Lage K., Pitteloud N.
Am. J. Hum. Genet. 92:725-743(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS HH17 MET-77; ASN-82; ARG-154; TYR-186; TYR-218; MET-258 AND ILE-281.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AF227516 mRNA. Translation: AAK00652.1. Different initiation.
AF227517 mRNA. Translation: AAK00653.1.
AY538661 Genomic DNA. Translation: AAS46253.1.
AK096464 mRNA. Translation: BAC04798.1.
AC091825 Genomic DNA. No translation available.
BC125095 mRNA. Translation: AAI25096.1.
BC125096 mRNA. Translation: AAI25097.1.
RefSeqNP_001120968.1. NM_001127496.1.
NP_112226.2. NM_030964.3.
XP_005268575.1. XM_005268518.2.
XP_005268576.1. XM_005268519.2.
UniGeneHs.323308.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
3BUNX-ray2.00A46-58[»]
ProteinModelPortalQ9C004.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid123599. 6 interactions.
IntActQ9C004. 2 interactions.
MINTMINT-6538953.
STRING9606.ENSP00000344967.

PTM databases

PhosphoSiteQ9C004.

Polymorphism databases

DMDM14916719.

Proteomic databases

PaxDbQ9C004.
PRIDEQ9C004.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000344120; ENSP00000344967; ENSG00000187678.
ENST00000434127; ENSP00000399468; ENSG00000187678. [Q9C004-1]
GeneID81848.
KEGGhsa:81848.
UCSCuc003lml.2. human. [Q9C004-1]

Organism-specific databases

CTD81848.
GeneCardsGC05M141670.
HGNCHGNC:15533. SPRY4.
HPACAB008086.
HPA055471.
MIM607984. gene.
615266. phenotype.
neXtProtNX_Q9C004.
Orphanet478. Kallmann syndrome.
432. Normosmic congenital hypogonadotropic hypogonadism.
363494. Testicular non seminomatous germ cell tumor.
842. Testicular seminomatous germ cell tumor.
PharmGKBPA37975.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG68509.
HOGENOMHOG000233079.
HOVERGENHBG003544.
InParanoidQ9C004.
KOK17385.
OrthoDBEOG7G4QDV.
PhylomeDBQ9C004.
TreeFamTF325070.

Enzyme and pathway databases

SignaLinkQ9C004.

Gene expression databases

ArrayExpressQ9C004.
BgeeQ9C004.
CleanExHS_SPRY4.
GenevestigatorQ9C004.

Family and domain databases

InterProIPR007875. Sprouty.
[Graphical view]
PfamPF05210. Sprouty. 1 hit.
[Graphical view]
PROSITEPS51227. SPR. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSSPRY4. human.
EvolutionaryTraceQ9C004.
GeneWikiSPRY4.
GenomeRNAi81848.
NextBio72154.
PROQ9C004.
SOURCESearch...

Entry information

Entry nameSPY4_HUMAN
AccessionPrimary (citable) accession number: Q9C004
Secondary accession number(s): A4FVB2 expand/collapse secondary AC list , A4FVB3, Q6QIX2, Q9C003
Entry history
Integrated into UniProtKB/Swiss-Prot: July 11, 2001
Last sequence update: July 11, 2001
Last modified: April 16, 2014
This is version 110 of the entry and version 2 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

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

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

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 5

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