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Protein

R-spondin-3

Gene

Rspo3

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: 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, which acts as a key regulator of angiogenesis (PubMed:16543246, PubMed:21693646, PubMed:26766444). 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. Acts as a ligand for frizzled FZD8 and LRP6. May negatively regulate the TGF-beta pathway (PubMed:16543246, PubMed:21693646). Acts as a key regulator of angiogenesis by controlling vascular stability and pruning: acts by activating the non-canonical Wnt signaling pathway in endothelial cells (PubMed:26766444).3 Publications

GO - Molecular functioni

  • frizzled binding Source: MGI
  • heparin binding Source: MGI
  • receptor binding Source: MGI

GO - Biological processi

  • angiogenesis Source: MGI
  • blood vessel remodeling Source: UniProtKB
  • branching involved in labyrinthine layer morphogenesis Source: MGI
  • positive regulation of canonical Wnt signaling pathway Source: MGI
  • positive regulation of non-canonical Wnt signaling pathway Source: UniProtKB
  • sprouting angiogenesis Source: UniProtKB
  • 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

ReactomeiR-MMU-4641263. Regulation of FZD by ubiquitination.

Names & Taxonomyi

Protein namesi
Recommended name:
R-spondin-3
Alternative name(s):
Cabriolet
Cysteine-rich and single thrombospondin domain-containing protein 11 Publication
Short name:
Cristin-11 Publication
Nucleopondin1 Publication
Roof plate-specific spondin-3
Gene namesi
Name:Rspo3
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 10

Organism-specific databases

MGIiMGI:1920030. Rspo3.

Subcellular locationi

  • Secreted 1 Publication

GO - Cellular componenti

  • extracellular region Source: MGI
Complete GO annotation...

Keywords - Cellular componenti

Secreted

Pathology & Biotechi

Disruption phenotypei

Embryonic lethality due to vascular remodeling defects (PubMed:26766444). Conditional knockout in endothelial cells results in impaired developmental and tumor vascular remodeling. Mice show endothelial cell apoptosis and vascular pruning, leading to reduced microvessel density (PubMed:26766444).1 Publication

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Signal peptidei1 – 2121Sequence analysisAdd
BLAST
Chaini22 – 277256R-spondin-3PRO_0000234444Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Glycosylationi36 – 361N-linked (GlcNAc...)Sequence analysis
Disulfide bondi41 ↔ 48PROSITE-ProRule annotation
Disulfide bondi45 ↔ 54PROSITE-ProRule annotation
Disulfide bondi57 ↔ 76PROSITE-ProRule annotation
Disulfide bondi80 ↔ 95PROSITE-ProRule annotation
Disulfide bondi98 ↔ 105PROSITE-ProRule annotation
Disulfide bondi102 ↔ 111PROSITE-ProRule annotation
Disulfide bondi114 ↔ 125PROSITE-ProRule annotation
Disulfide bondi129 ↔ 142PROSITE-ProRule annotation
Disulfide bondi148 ↔ 190PROSITE-ProRule annotation
Disulfide bondi159 ↔ 166PROSITE-ProRule annotation
Disulfide bondi199 ↔ 206PROSITE-ProRule annotation

Keywords - PTMi

Disulfide bond, Glycoprotein

Proteomic databases

PaxDbiQ2TJ95.
PRIDEiQ2TJ95.

PTM databases

iPTMnetiQ2TJ95.
PhosphoSiteiQ2TJ95.

Expressioni

Tissue specificityi

Highly expressed in endothelial cells (PubMed:26766444).1 Publication

Developmental stagei

Expressed from day 7.5 in the primitive streak. At day 9.5, it is expressed in various neural and mesodermal derivatives, mainly along dorsal neural tube, diencephalon, somites and tailbud mesoderm. Strongly expressed in limb buds, particularly in the morphogenetically active region such as the apical ectodermal ridge (AER).1 Publication

Gene expression databases

BgeeiQ2TJ95.
CleanExiMM_RSPO3.
GenevisibleiQ2TJ95. MM.

Interactioni

Subunit structurei

Interacts with the extracellular domain of FZD8 and LRP6 (PubMed:16543246). It however does not form a ternary complex with FZD8 and LRP6 (PubMed:16543246). Interacts with WNT1 (PubMed:16543246). Binds heparin. Interacts with LGR4, LGR5 and LGR6 (PubMed:21693646).2 Publications

GO - Molecular functioni

  • frizzled binding Source: MGI
  • receptor binding Source: MGI

Protein-protein interaction databases

STRINGi10090.ENSMUSP00000090287.

Structurei

3D structure databases

ProteinModelPortaliQ2TJ95.
SMRiQ2TJ95. Positions 53-130.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Repeati35 – 8652FU 1Add
BLAST
Repeati92 – 13544FU 2Add
BLAST
Domaini147 – 20761TSP type-1PROSITE-ProRule annotationAdd
BLAST

Domaini

The FU repeats are required for activation and stabilization of beta-catenin.1 Publication

Sequence similaritiesi

Belongs to the R-spondin family.Curated
Contains 2 FU (furin-like) repeats.Curated
Contains 1 TSP type-1 domain.PROSITE-ProRule annotation

Keywords - Domaini

Repeat, Signal

Phylogenomic databases

eggNOGiKOG3525. Eukaryota.
COG1404. LUCA.
GeneTreeiENSGT00390000011447.
HOGENOMiHOG000290668.
HOVERGENiHBG082751.
InParanoidiQ2TJ95.
OMAiMECTSIV.
OrthoDBiEOG7X9G7G.
PhylomeDBiQ2TJ95.
TreeFamiTF331799.

Family and domain databases

InterProiIPR006212. Furin_repeat.
IPR009030. Growth_fac_rcpt_.
IPR000884. TSP1_rpt.
[Graphical view]
PfamiPF15913. Furin-like_2. 1 hit.
[Graphical view]
SMARTiSM00261. FU. 2 hits.
SM00209. TSP1. 1 hit.
[Graphical view]
SUPFAMiSSF57184. SSF57184. 1 hit.
SSF82895. SSF82895. 1 hit.
PROSITEiPS50092. TSP1. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

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

Q2TJ95-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MHLRLISCFF IILNFMEYIG SQNASRGRRQ RRMHPNVSQG CQGGCATCSD
60 70 80 90 100
YNGCLSCKPR LFFVLERIGM KQIGVCLSSC PSGYYGTRYP DINKCTKCKV
110 120 130 140 150
DCDTCFNKNF CTKCKSGFYL HLGKCLDSCP EGLEANNHTM ECVSIVHCEA
160 170 180 190 200
SEWSPWSPCM KKGKTCGFKR GTETRVRDIL QHPSAKGNLC PPTSETRTCI
210 220 230 240 250
VQRKKCSKGE RGKKGRERKR KKLNKEERKE TSSSSDSKGL ESSIETPDQQ
260 270
ENKERQQQQK RRARDKQQKS VSVSTVH
Length:277
Mass (Da):31,454
Last modified:May 16, 2006 - v2
Checksum:i9C5AD3A48AFF8C66
GO

Sequence cautioni

The sequence BAC36296.1 differs from that shown. Reason: Frameshift at position 189. Curated

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti108 – 1081K → Q in AAX57441 (PubMed:16543246).Curated
Sequence conflicti108 – 1081K → Q in BAC36296 (PubMed:15489334).Curated
Sequence conflicti130 – 1301P → A in BAC41353 (Ref. 2) Curated
Sequence conflicti170 – 1701R → G in BAB28811 (PubMed:15489334).Curated

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AY864332 mRNA. Translation: AAX57441.1.
AB055811 mRNA. Translation: BAC41353.1.
AK013366 mRNA. Translation: BAB28811.1.
AK076308 mRNA. Translation: BAC36296.1. Frameshift.
BC103794 mRNA. Translation: AAI03795.1.
BC145929 mRNA. Translation: AAI45930.1.
BC145931 mRNA. Translation: AAI45932.1.
CCDSiCCDS23761.1.
RefSeqiNP_082627.3. NM_028351.3.
UniGeneiMm.45191.

Genome annotation databases

EnsembliENSMUST00000092623; ENSMUSP00000090287; ENSMUSG00000019880.
GeneIDi72780.
KEGGimmu:72780.
UCSCiuc007etb.2. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AY864332 mRNA. Translation: AAX57441.1.
AB055811 mRNA. Translation: BAC41353.1.
AK013366 mRNA. Translation: BAB28811.1.
AK076308 mRNA. Translation: BAC36296.1. Frameshift.
BC103794 mRNA. Translation: AAI03795.1.
BC145929 mRNA. Translation: AAI45930.1.
BC145931 mRNA. Translation: AAI45932.1.
CCDSiCCDS23761.1.
RefSeqiNP_082627.3. NM_028351.3.
UniGeneiMm.45191.

3D structure databases

ProteinModelPortaliQ2TJ95.
SMRiQ2TJ95. Positions 53-130.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

STRINGi10090.ENSMUSP00000090287.

PTM databases

iPTMnetiQ2TJ95.
PhosphoSiteiQ2TJ95.

Proteomic databases

PaxDbiQ2TJ95.
PRIDEiQ2TJ95.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000092623; ENSMUSP00000090287; ENSMUSG00000019880.
GeneIDi72780.
KEGGimmu:72780.
UCSCiuc007etb.2. mouse.

Organism-specific databases

CTDi84870.
MGIiMGI:1920030. Rspo3.

Phylogenomic databases

eggNOGiKOG3525. Eukaryota.
COG1404. LUCA.
GeneTreeiENSGT00390000011447.
HOGENOMiHOG000290668.
HOVERGENiHBG082751.
InParanoidiQ2TJ95.
OMAiMECTSIV.
OrthoDBiEOG7X9G7G.
PhylomeDBiQ2TJ95.
TreeFamiTF331799.

Enzyme and pathway databases

ReactomeiR-MMU-4641263. Regulation of FZD by ubiquitination.

Miscellaneous databases

PROiQ2TJ95.
SOURCEiSearch...

Gene expression databases

BgeeiQ2TJ95.
CleanExiMM_RSPO3.
GenevisibleiQ2TJ95. MM.

Family and domain databases

InterProiIPR006212. Furin_repeat.
IPR009030. Growth_fac_rcpt_.
IPR000884. TSP1_rpt.
[Graphical view]
PfamiPF15913. Furin-like_2. 1 hit.
[Graphical view]
SMARTiSM00261. FU. 2 hits.
SM00209. TSP1. 1 hit.
[Graphical view]
SUPFAMiSSF57184. SSF57184. 1 hit.
SSF82895. SSF82895. 1 hit.
PROSITEiPS50092. TSP1. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "Mouse cristin/R-spondin family proteins are novel ligands for the Frizzled 8 and LRP6 receptors and activate beta-catenin-dependent gene expression."
    Nam J.-S., Turcotte T.J., Smith P.F., Choi S., Yoon J.K.
    J. Biol. Chem. 281:13247-13257(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBCELLULAR LOCATION, HEPARIN-BINDING, DOMAIN, INTERACTION WITH FZD8; LRP6 AND WNT1.
  2. "Nucleopondin, a novel nuclear protein with a thrombospondin type I repeat, is expressed in dynamic spatial and temporal patterns in zebrafish and mouse development."
    Mieda M., Hirate Y., Aoki M., Sasaki K., Okamoto H.
    Submitted (FEB-2001) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [MRNA].
  3. "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].
    Tissue: Brain and Limb.
  4. "The transcriptional landscape of the mammalian genome."
    Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.
    , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.
    Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    Strain: C57BL/6J.
    Tissue: Skin.
  5. "R-Spondin2 is a secreted activator of Wnt/beta-catenin signaling and is required for Xenopus myogenesis."
    Kazanskaya O., Glinka A., del Barco Barrantes I., Stannek P., Niehrs C., Wu W.
    Dev. Cell 7:525-534(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: DEVELOPMENTAL STAGE.
  6. "R-spondins function as ligands of the orphan receptors LGR4 and LGR5 to regulate Wnt/beta-catenin signaling."
    Carmon K.S., Gong X., Lin Q., Thomas A., Liu Q.
    Proc. Natl. Acad. Sci. U.S.A. 108:11452-11457(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, INTERACTION WITH LGR4 AND LGR5.
  7. "Endothelial RSPO3 controls vascular stability and pruning through non-canonical WNT/Ca(2+)/NFAT signaling."
    Scholz B., Korn C., Wojtarowicz J., Mogler C., Augustin I., Boutros M., Niehrs C., Augustin H.G.
    Dev. Cell 36:79-93(2016) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, DISRUPTION PHENOTYPE, TISSUE SPECIFICITY.

Entry informationi

Entry nameiRSPO3_MOUSE
AccessioniPrimary (citable) accession number: Q2TJ95
Secondary accession number(s): A6H6M4
, Q3SYI9, Q5R2V4, Q8BVW2, Q9CSB2
Entry historyi
Integrated into UniProtKB/Swiss-Prot: May 16, 2006
Last sequence update: May 16, 2006
Last modified: June 8, 2016
This is version 90 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.