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Q2I0M5

- RSPO4_HUMAN

UniProt

Q2I0M5 - RSPO4_HUMAN

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Protein

R-spondin-4

Gene

RSPO4

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli

Functioni

Activator of the canonical Wnt signaling pathway by acting as a ligand for LGR4-6 receptors. Upon binding to LGR4-6 (LGR4, LGR5 or LGR6), LGR4-6 associate with phosphorylated LRP6 and frizzled receptors that are activated by extracellular Wnt receptors, triggering the canonical Wnt signaling pathway to increase expression of target genes. Also regulates the canonical Wnt/beta-catenin-dependent pathway and non-canonical Wnt signaling by acting as an inhibitor of ZNRF3, an important regulator of the Wnt signaling pathway.2 Publications

GO - Molecular functioni

  1. heparin binding Source: UniProtKB-KW

GO - Biological processi

  1. Wnt signaling pathway Source: UniProtKB-KW
Complete GO annotation...

Keywords - Biological processi

Sensory transduction, Wnt signaling pathway

Keywords - Ligandi

Heparin-binding

Enzyme and pathway databases

ReactomeiREACT_200716. regulation of FZD by ubiquitination.

Names & Taxonomyi

Protein namesi
Recommended name:
R-spondin-4
Alternative name(s):
Roof plate-specific spondin-4
Short name:
hRspo4
Gene namesi
Name:RSPO4
Synonyms:C20orf182
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640: Chromosome 20

Organism-specific databases

HGNCiHGNC:16175. RSPO4.

Subcellular locationi

Secreted By similarity

GO - Cellular componenti

  1. extracellular region Source: UniProtKB-KW
Complete GO annotation...

Keywords - Cellular componenti

Secreted

Pathology & Biotechi

Involvement in diseasei

Nail disorder, non-syndromic congenital, 4 (NDNC4) [MIM:206800]: A nail disorder characterized by congenital anonychia or its milder phenotypic variant hyponychia. Anonychia/hyponychia is the absence or severe hypoplasia of all fingernails and toenails without significant bone anomalies.1 Publication
Note: The disease is caused by mutations affecting the gene represented in this entry.
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti65 – 651Q → R in NDNC4. 1 Publication
VAR_030399
Natural varianti95 – 951C → F in NDNC4. 1 Publication
VAR_030400
Natural varianti107 – 1071C → R in NDNC4. 1 Publication
VAR_030401
Natural varianti118 – 1181C → Y in NDNC4. 1 Publication
VAR_030402

Keywords - Diseasei

Disease mutation

Organism-specific databases

MIMi206800. phenotype.
Orphaneti79143. Congenital anonychia.
PharmGKBiPA25726.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Signal peptidei1 – 1919Sequence AnalysisAdd
BLAST
Chaini20 – 234215R-spondin-4PRO_0000234446Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Glycosylationi34 – 341N-linked (GlcNAc...)Sequence Analysis
Disulfide bondi35 ↔ 41PROSITE-ProRule annotation
Disulfide bondi38 ↔ 47PROSITE-ProRule annotation
Disulfide bondi50 ↔ 69PROSITE-ProRule annotation
Disulfide bondi73 ↔ 88PROSITE-ProRule annotation
Disulfide bondi91 ↔ 98PROSITE-ProRule annotation
Disulfide bondi95 ↔ 104PROSITE-ProRule annotation
Disulfide bondi107 ↔ 118PROSITE-ProRule annotation
Disulfide bondi122 ↔ 135PROSITE-ProRule annotation
Disulfide bondi139 ↔ 181PROSITE-ProRule annotation
Disulfide bondi150 ↔ 157PROSITE-ProRule annotation
Disulfide bondi190 ↔ 196PROSITE-ProRule annotation

Post-translational modificationi

Tyr-112 may be phosphorylated; however as this position is probably extracellular, the vivo relevance is not proven.

Keywords - PTMi

Disulfide bond, Glycoprotein, Phosphoprotein

Proteomic databases

PaxDbiQ2I0M5.
PRIDEiQ2I0M5.

PTM databases

PhosphoSiteiQ2I0M5.

Expressioni

Gene expression databases

BgeeiQ2I0M5.
CleanExiHS_RSPO4.
GenevestigatoriQ2I0M5.

Organism-specific databases

HPAiHPA048887.

Interactioni

Subunit structurei

Binds heparin By similarity. Interacts with LGR4, LGR5 and LGR6.By similarity2 Publications

Protein-protein interaction databases

BioGridi131268. 2 interactions.

Structurei

3D structure databases

ProteinModelPortaliQ2I0M5.
SMRiQ2I0M5. Positions 35-135.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Repeati85 – 12844FUAdd
BLAST
Domaini138 – 19760TSP type-1PROSITE-ProRule annotationAdd
BLAST

Domaini

The FU repeat is required for activation and stabilization of beta-catenin.By similarity

Sequence similaritiesi

Belongs to the R-spondin family.Curated
Contains 1 FU (furin-like) repeat.Curated
Contains 1 TSP type-1 domain.PROSITE-ProRule annotation

Keywords - Domaini

Signal

Phylogenomic databases

eggNOGiNOG256987.
GeneTreeiENSGT00390000011447.
HOGENOMiHOG000290668.
HOVERGENiHBG082751.
InParanoidiQ2I0M5.
OMAiRPCPGER.
OrthoDBiEOG7X9G7G.
PhylomeDBiQ2I0M5.
TreeFamiTF331799.

Family and domain databases

InterProiIPR006212. Furin_repeat.
IPR009030. Growth_fac_rcpt_N_dom.
IPR000884. Thrombospondin_1_rpt.
[Graphical view]
SMARTiSM00261. FU. 2 hits.
SM00209. TSP1. 1 hit.
[Graphical view]
SUPFAMiSSF57184. SSF57184. 1 hit.
PROSITEiPS50092. TSP1. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

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

This entry describes 2 isoformsi produced by alternative splicing. Align

Isoform 1 (identifier: Q2I0M5-1) [UniParc]FASTAAdd to Basket

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.

« Hide

        10         20         30         40         50
MRAPLCLLLL VAHAVDMLAL NRRKKQVGTG LGGNCTGCII CSEENGCSTC
60 70 80 90 100
QQRLFLFIRR EGIRQYGKCL HDCPPGYFGI RGQEVNRCKK CGATCESCFS
110 120 130 140 150
QDFCIRCKRQ FYLYKGKCLP TCPPGTLAHQ NTRECQGECE LGPWGGWSPC
160 170 180 190 200
THNGKTCGSA WGLESRVREA GRAGHEEAAT CQVLSESRKC PIQRPCPGER
210 220 230
SPGQKKGRKD RRPRKDRKLD RRLDVRPRQP GLQP
Length:234
Mass (Da):26,171
Last modified:May 16, 2006 - v2
Checksum:i853E4494533B73F7
GO
Isoform 2 (identifier: Q2I0M5-2) [UniParc]FASTAAdd to Basket

The sequence of this isoform differs from the canonical sequence as follows:
     137-198: Missing.

Show »
Length:172
Mass (Da):19,607
Checksum:iD74D391A7B4E902E
GO

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti65 – 651Q → R in NDNC4. 1 Publication
VAR_030399
Natural varianti95 – 951C → F in NDNC4. 1 Publication
VAR_030400
Natural varianti106 – 1061R → Q.
Corresponds to variant rs6140807 [ dbSNP | Ensembl ].
VAR_052665
Natural varianti107 – 1071C → R in NDNC4. 1 Publication
VAR_030401
Natural varianti118 – 1181C → Y in NDNC4. 1 Publication
VAR_030402

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei137 – 19862Missing in isoform 2. 1 PublicationVSP_018325Add
BLAST

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
DQ355152 mRNA. Translation: ABC75877.1.
AK122609 mRNA. No translation available.
AL050325 Genomic DNA. Translation: CAB65783.4.
AL050325 Genomic DNA. Translation: CAM28322.1.
CCDSiCCDS42845.1. [Q2I0M5-2]
CCDS42846.1. [Q2I0M5-1]
RefSeqiNP_001025042.2. NM_001029871.3. [Q2I0M5-1]
NP_001035096.1. NM_001040007.2. [Q2I0M5-2]
UniGeneiHs.444980.

Genome annotation databases

EnsembliENST00000217260; ENSP00000217260; ENSG00000101282. [Q2I0M5-1]
ENST00000400634; ENSP00000383475; ENSG00000101282. [Q2I0M5-2]
GeneIDi343637.
KEGGihsa:343637.
UCSCiuc002wej.3. human. [Q2I0M5-1]
uc002wek.3. human. [Q2I0M5-2]

Polymorphism databases

DMDMi97189858.

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
DQ355152 mRNA. Translation: ABC75877.1 .
AK122609 mRNA. No translation available.
AL050325 Genomic DNA. Translation: CAB65783.4 .
AL050325 Genomic DNA. Translation: CAM28322.1 .
CCDSi CCDS42845.1. [Q2I0M5-2 ]
CCDS42846.1. [Q2I0M5-1 ]
RefSeqi NP_001025042.2. NM_001029871.3. [Q2I0M5-1 ]
NP_001035096.1. NM_001040007.2. [Q2I0M5-2 ]
UniGenei Hs.444980.

3D structure databases

ProteinModelPortali Q2I0M5.
SMRi Q2I0M5. Positions 35-135.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 131268. 2 interactions.

PTM databases

PhosphoSitei Q2I0M5.

Polymorphism databases

DMDMi 97189858.

Proteomic databases

PaxDbi Q2I0M5.
PRIDEi Q2I0M5.

Protocols and materials databases

DNASUi 343637.
Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENST00000217260 ; ENSP00000217260 ; ENSG00000101282 . [Q2I0M5-1 ]
ENST00000400634 ; ENSP00000383475 ; ENSG00000101282 . [Q2I0M5-2 ]
GeneIDi 343637.
KEGGi hsa:343637.
UCSCi uc002wej.3. human. [Q2I0M5-1 ]
uc002wek.3. human. [Q2I0M5-2 ]

Organism-specific databases

CTDi 343637.
GeneCardsi GC20M000890.
HGNCi HGNC:16175. RSPO4.
HPAi HPA048887.
MIMi 206800. phenotype.
610573. gene.
neXtProti NX_Q2I0M5.
Orphaneti 79143. Congenital anonychia.
PharmGKBi PA25726.
GenAtlasi Search...

Phylogenomic databases

eggNOGi NOG256987.
GeneTreei ENSGT00390000011447.
HOGENOMi HOG000290668.
HOVERGENi HBG082751.
InParanoidi Q2I0M5.
OMAi RPCPGER.
OrthoDBi EOG7X9G7G.
PhylomeDBi Q2I0M5.
TreeFami TF331799.

Enzyme and pathway databases

Reactomei REACT_200716. regulation of FZD by ubiquitination.

Miscellaneous databases

GenomeRNAii 343637.
NextBioi 98588.
PROi Q2I0M5.
SOURCEi Search...

Gene expression databases

Bgeei Q2I0M5.
CleanExi HS_RSPO4.
Genevestigatori Q2I0M5.

Family and domain databases

InterProi IPR006212. Furin_repeat.
IPR009030. Growth_fac_rcpt_N_dom.
IPR000884. Thrombospondin_1_rpt.
[Graphical view ]
SMARTi SM00261. FU. 2 hits.
SM00209. TSP1. 1 hit.
[Graphical view ]
SUPFAMi SSF57184. SSF57184. 1 hit.
PROSITEi PS50092. TSP1. 1 hit.
[Graphical view ]
ProtoNeti Search...

Publicationsi

« Hide 'large scale' publications
  1. "R-spondin proteins: a novel link to beta-catenin activation."
    Kim K.-A., Zhao J., Andarmani S., Kakitani M., Oshima T., Binnerts M.E., Abo A., Tomizuka K., Funk W.D.
    Cell Cycle 5:23-26(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), INJECTION INTO MICE.
  2. "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] (ISOFORM 1).
    Tissue: Glial tumor.
  3. "The DNA sequence and comparative analysis of human chromosome 20."
    Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R., Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L., Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M., Beasley O.P., Bird C.P., Blakey S.E.
    , Bridgeman A.M., Brown A.J., Buck D., Burrill W.D., Butler A.P., Carder C., Carter N.P., Chapman J.C., Clamp M., Clark G., Clark L.N., Clark S.Y., Clee C.M., Clegg S., Cobley V.E., Collier R.E., Connor R.E., Corby N.R., Coulson A., Coville G.J., Deadman R., Dhami P.D., Dunn M., Ellington A.G., Frankland J.A., Fraser A., French L., Garner P., Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E., Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J., Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D., Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S., Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D., Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A., Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T., Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I., Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H., Rice C.M., Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., Skuce C.D., Smith M.L., Soderlund C., Steward C.A., Sulston J.E., Swann R.M., Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., Tracey A., Tromans A.C., Vaudin M., Wall M., Wallis J.M., Whitehead S.L., Whittaker P., Willey D.L., Williams L., Williams S.A., Wilming L., Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., Rogers J.
    Nature 414:865-871(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
  4. "Robust phosphoproteomic profiling of tyrosine phosphorylation sites from human T cells using immobilized metal affinity chromatography and tandem mass spectrometry."
    Brill L.M., Salomon A.R., Ficarro S.B., Mukherji M., Stettler-Gill M., Peters E.C.
    Anal. Chem. 76:2763-2772(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Leukemic T-cell.
  5. "LGR4 and LGR5 are R-spondin receptors mediating Wnt/beta-catenin and Wnt/PCP signalling."
    Glinka A., Dolde C., Kirsch N., Huang Y.L., Kazanskaya O., Ingelfinger D., Boutros M., Cruciat C.M., Niehrs C.
    EMBO Rep. 12:1055-1061(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, INTERACTION WITH LGR4 AND LGR5.
  6. Cited for: FUNCTION, INTERACTION WITH LGR4; LGR5 AND LGR6.
  7. "The gene encoding R-spondin 4 (RSPO4), a secreted protein implicated in Wnt signaling, is mutated in inherited anonychia."
    Blaydon D.C., Ishii Y., O'Toole E.A., Unsworth H.C., Teh M.-T., Rueschendorf F., Sinclair C., Hopsu-Havu V.K., Tidman N., Moss C., Watson R., de Berker D., Wajid M., Christiano A.M., Kelsell D.P.
    Nat. Genet. 38:1245-1247(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: VARIANTS NDNC4 ARG-65; PHE-95; ARG-107 AND TYR-118.

Entry informationi

Entry nameiRSPO4_HUMAN
AccessioniPrimary (citable) accession number: Q2I0M5
Secondary accession number(s): A2A2I6, Q9UGB2
Entry historyi
Integrated into UniProtKB/Swiss-Prot: May 16, 2006
Last sequence update: May 16, 2006
Last modified: October 29, 2014
This is version 84 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (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.

Miscellaneousi

Miscellaneous

Upon injection into mice, it induces rapid onset of crypt cell proliferation involving beta-catenin stabilization. It also displays efficacy in a model of chemotherapy-induced intestinal mucositis (PubMed:16357527).1 Publication

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human chromosome 20
    Human chromosome 20: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3