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Q2I0M5

- RSPO4_HUMAN

UniProt

Q2I0M5 - RSPO4_HUMAN

Protein

R-spondin-4

Gene

RSPO4

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 83 (01 Oct 2014)
      Sequence version 2 (16 May 2006)
      Previous versions | rss
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    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

    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-SubCell

    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 35-161.
    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.
    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

    MRAPLCLLLL VAHAVDMLAL NRRKKQVGTG LGGNCTGCII CSEENGCSTC    50
    QQRLFLFIRR EGIRQYGKCL HDCPPGYFGI RGQEVNRCKK CGATCESCFS 100
    QDFCIRCKRQ FYLYKGKCLP TCPPGTLAHQ NTRECQGECE LGPWGGWSPC 150
    THNGKTCGSA WGLESRVREA GRAGHEEAAT CQVLSESRKC PIQRPCPGER 200
    SPGQKKGRKD RRPRKDRKLD RRLDVRPRQP GLQP 234
    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 35-161.
    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.
    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

    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 1, 2014
    This is version 83 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