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Q2I0M5 (RSPO4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 81. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (5) | 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:
R-spondin-4
Alternative name(s):
Roof plate-specific spondin-4
Short name=hRspo4
Gene names
Name:RSPO4
Synonyms:C20orf182
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length234 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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. Ref.5 Ref.6

Subunit structure

Binds heparin By similarity. Interacts with LGR4, LGR5 and LGR6. Ref.5 Ref.6

Subcellular location

Secreted By similarity.

Domain

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

Post-translational modification

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

Involvement in disease

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.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.7

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 (Ref.1).

Sequence similarities

Belongs to the R-spondin family.

Contains 1 FU (furin-like) repeat.

Contains 1 TSP type-1 domain.

Ontologies

Keywords
   Biological processSensory transduction
Wnt signaling pathway
   Cellular componentSecreted
   Coding sequence diversityAlternative splicing
Polymorphism
   DiseaseDisease mutation
   DomainSignal
   LigandHeparin-binding
   PTMDisulfide bond
Glycoprotein
Phosphoprotein
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processWnt signaling pathway

Inferred from electronic annotation. Source: UniProtKB-KW

   Cellular_componentextracellular region

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular_functionheparin binding

Inferred from electronic annotation. Source: UniProtKB-KW

Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: Q2I0M5-1)

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: Q2I0M5-2)

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

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 1919 Potential
Chain20 – 234215R-spondin-4
PRO_0000234446

Regions

Repeat85 – 12844FU
Domain138 – 19760TSP type-1

Amino acid modifications

Glycosylation341N-linked (GlcNAc...) Potential
Disulfide bond35 ↔ 41 By similarity
Disulfide bond38 ↔ 47 By similarity
Disulfide bond50 ↔ 69 By similarity
Disulfide bond73 ↔ 88 By similarity
Disulfide bond91 ↔ 98 By similarity
Disulfide bond95 ↔ 104 By similarity
Disulfide bond107 ↔ 118 By similarity
Disulfide bond122 ↔ 135 By similarity
Disulfide bond139 ↔ 181 By similarity
Disulfide bond150 ↔ 157 By similarity
Disulfide bond190 ↔ 196 By similarity

Natural variations

Alternative sequence137 – 19862Missing in isoform 2.
VSP_018325
Natural variant651Q → R in NDNC4. Ref.7
VAR_030399
Natural variant951C → F in NDNC4. Ref.7
VAR_030400
Natural variant1061R → Q.
Corresponds to variant rs6140807 [ dbSNP | Ensembl ].
VAR_052665
Natural variant1071C → R in NDNC4. Ref.7
VAR_030401
Natural variant1181C → Y in NDNC4. Ref.7
VAR_030402

Sequences

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

Last modified May 16, 2006. Version 2.
Checksum: 853E4494533B73F7

FASTA23426,171
        10         20         30         40         50         60 
MRAPLCLLLL VAHAVDMLAL NRRKKQVGTG LGGNCTGCII CSEENGCSTC QQRLFLFIRR 

        70         80         90        100        110        120 
EGIRQYGKCL HDCPPGYFGI RGQEVNRCKK CGATCESCFS QDFCIRCKRQ FYLYKGKCLP 

       130        140        150        160        170        180 
TCPPGTLAHQ NTRECQGECE LGPWGGWSPC THNGKTCGSA WGLESRVREA GRAGHEEAAT 

       190        200        210        220        230 
CQVLSESRKC PIQRPCPGER SPGQKKGRKD RRPRKDRKLD RRLDVRPRQP GLQP 

« Hide

Isoform 2 [UniParc].

Checksum: D74D391A7B4E902E
Show »

FASTA17219,607

References

« Hide 'large scale' references
[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. 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 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. expand/collapse author list , 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]"Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling."
de Lau W., Barker N., Low T.Y., Koo B.K., Li V.S., Teunissen H., Kujala P., Haegebarth A., Peters P.J., van de Wetering M., Stange D.E., van Es J.E., Guardavaccaro D., Schasfoort R.B., Mohri Y., Nishimori K., Mohammed S., Heck A.J., Clevers H.
Nature 476:293-297(2011) [PubMed] [Europe PMC] [Abstract]
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.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
DQ355152 mRNA. Translation: ABC75877.1.
AK122609 mRNA. No translation available.
AL050325 Genomic DNA. Translation: CAB65783.4.
AL050325 Genomic DNA. Translation: CAM28322.1.
CCDSCCDS42845.1. [Q2I0M5-2]
CCDS42846.1. [Q2I0M5-1]
RefSeqNP_001025042.2. NM_001029871.3. [Q2I0M5-1]
NP_001035096.1. NM_001040007.2. [Q2I0M5-2]
UniGeneHs.444980.

3D structure databases

ProteinModelPortalQ2I0M5.
SMRQ2I0M5. Positions 35-161.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid131268. 2 interactions.

PTM databases

PhosphoSiteQ2I0M5.

Polymorphism databases

DMDM97189858.

Proteomic databases

PaxDbQ2I0M5.
PRIDEQ2I0M5.

Protocols and materials databases

DNASU343637.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000217260; ENSP00000217260; ENSG00000101282. [Q2I0M5-1]
ENST00000400634; ENSP00000383475; ENSG00000101282. [Q2I0M5-2]
GeneID343637.
KEGGhsa:343637.
UCSCuc002wej.3. human. [Q2I0M5-1]
uc002wek.3. human. [Q2I0M5-2]

Organism-specific databases

CTD343637.
GeneCardsGC20M000890.
HGNCHGNC:16175. RSPO4.
HPAHPA048887.
MIM206800. phenotype.
610573. gene.
neXtProtNX_Q2I0M5.
Orphanet79143. Congenital anonychia.
PharmGKBPA25726.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG256987.
HOGENOMHOG000290668.
HOVERGENHBG082751.
InParanoidQ2I0M5.
OMARPCPGER.
OrthoDBEOG7X9G7G.
PhylomeDBQ2I0M5.
TreeFamTF331799.

Enzyme and pathway databases

ReactomeREACT_111102. Signal Transduction.

Gene expression databases

BgeeQ2I0M5.
CleanExHS_RSPO4.
GenevestigatorQ2I0M5.

Family and domain databases

InterProIPR006212. Furin_repeat.
IPR009030. Growth_fac_rcpt_N_dom.
IPR000884. Thrombospondin_1_rpt.
[Graphical view]
SMARTSM00261. FU. 2 hits.
SM00209. TSP1. 1 hit.
[Graphical view]
SUPFAMSSF57184. SSF57184. 1 hit.
PROSITEPS50092. TSP1. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

GenomeRNAi343637.
NextBio98588.
PROQ2I0M5.
SOURCESearch...

Entry information

Entry nameRSPO4_HUMAN
AccessionPrimary (citable) accession number: Q2I0M5
Secondary accession number(s): A2A2I6, Q9UGB2
Entry history
Integrated into UniProtKB/Swiss-Prot: May 16, 2006
Last sequence update: May 16, 2006
Last modified: July 9, 2014
This is version 81 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

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 20

Human chromosome 20: entries, gene names and cross-references to MIM