RSPO3_MOUSE
ID RSPO3_MOUSE Reviewed; 277 AA.
AC Q2TJ95; A6H6M4; Q3SYI9; Q5R2V4; Q8BVW2; Q9CSB2;
DT 16-MAY-2006, integrated into UniProtKB/Swiss-Prot.
DT 16-MAY-2006, sequence version 2.
DT 03-AUG-2022, entry version 124.
DE RecName: Full=R-spondin-3;
DE AltName: Full=Cabriolet;
DE AltName: Full=Cysteine-rich and single thrombospondin domain-containing protein 1 {ECO:0000303|PubMed:16543246};
DE Short=Cristin-1 {ECO:0000303|PubMed:16543246};
DE AltName: Full=Nucleopondin {ECO:0000303|Ref.2};
DE AltName: Full=Roof plate-specific spondin-3;
DE Flags: Precursor;
GN Name=Rspo3;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBCELLULAR LOCATION,
RP HEPARIN-BINDING, DOMAIN, AND INTERACTION WITH FZD8; LRP6 AND WNT1.
RX PubMed=16543246; DOI=10.1074/jbc.m508324200;
RA Nam J.-S., Turcotte T.J., Smith P.F., Choi S., Yoon J.K.;
RT "Mouse cristin/R-spondin family proteins are novel ligands for the Frizzled
RT 8 and LRP6 receptors and activate beta-catenin-dependent gene expression.";
RL J. Biol. Chem. 281:13247-13257(2006).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Mieda M., Hirate Y., Aoki M., Sasaki K., Okamoto H.;
RT "Nucleopondin, a novel nuclear protein with a thrombospondin type I repeat,
RT is expressed in dynamic spatial and temporal patterns in zebrafish and
RT mouse development.";
RL Submitted (FEB-2001) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain, and Limb;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Skin;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [5]
RP DEVELOPMENTAL STAGE.
RX PubMed=15469841; DOI=10.1016/j.devcel.2004.07.019;
RA Kazanskaya O., Glinka A., del Barco Barrantes I., Stannek P., Niehrs C.,
RA Wu W.;
RT "R-Spondin2 is a secreted activator of Wnt/beta-catenin signaling and is
RT required for Xenopus myogenesis.";
RL Dev. Cell 7:525-534(2004).
RN [6]
RP FUNCTION, AND INTERACTION WITH LGR4 AND LGR5.
RX PubMed=21693646; DOI=10.1073/pnas.1106083108;
RA Carmon K.S., Gong X., Lin Q., Thomas A., Liu Q.;
RT "R-spondins function as ligands of the orphan receptors LGR4 and LGR5 to
RT regulate Wnt/beta-catenin signaling.";
RL Proc. Natl. Acad. Sci. U.S.A. 108:11452-11457(2011).
RN [7]
RP FUNCTION, DISRUPTION PHENOTYPE, AND TISSUE SPECIFICITY.
RX PubMed=26766444; DOI=10.1016/j.devcel.2015.12.015;
RA Scholz B., Korn C., Wojtarowicz J., Mogler C., Augustin I., Boutros M.,
RA Niehrs C., Augustin H.G.;
RT "Endothelial RSPO3 controls vascular stability and pruning through non-
RT canonical WNT/Ca(2+)/NFAT signaling.";
RL Dev. Cell 36:79-93(2016).
CC -!- FUNCTION: Activator of the canonical Wnt signaling pathway by acting as
CC a ligand for LGR4-6 receptors, which acts as a key regulator of
CC angiogenesis (PubMed:16543246, PubMed:21693646, PubMed:26766444). Upon
CC binding to LGR4-6 (LGR4, LGR5 or LGR6), LGR4-6 associate with
CC phosphorylated LRP6 and frizzled receptors that are activated by
CC extracellular Wnt receptors, triggering the canonical Wnt signaling
CC pathway to increase expression of target genes. Also regulates the
CC canonical Wnt/beta-catenin-dependent pathway and non-canonical Wnt
CC signaling by acting as an inhibitor of ZNRF3, an important regulator of
CC the Wnt signaling pathway. Acts as a ligand for frizzled FZD8 and LRP6.
CC May negatively regulate the TGF-beta pathway (PubMed:16543246,
CC PubMed:21693646). Acts as a key regulator of angiogenesis by
CC controlling vascular stability and pruning: acts by activating the non-
CC canonical Wnt signaling pathway in endothelial cells (PubMed:26766444,
CC PubMed:16543246, PubMed:21693646). Can also amplify Wnt signaling
CC pathway independently of LGR4-6 receptors, possibly by acting as a
CC direct antagonistic ligand to RNF43 and ZNRF3 (By similarity).
CC {ECO:0000250|UniProtKB:Q9BXY4, ECO:0000269|PubMed:16543246,
CC ECO:0000269|PubMed:21693646, ECO:0000269|PubMed:26766444}.
CC -!- SUBUNIT: Interacts with the extracellular domain of FZD8 and LRP6
CC (PubMed:16543246). It however does not form a ternary complex with FZD8
CC and LRP6 (PubMed:16543246). Interacts with WNT1 (PubMed:16543246).
CC Binds heparin. Interacts with LGR4, LGR5 and LGR6 (PubMed:21693646).
CC {ECO:0000269|PubMed:16543246, ECO:0000269|PubMed:21693646}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:16543246}.
CC -!- TISSUE SPECIFICITY: Highly expressed in endothelial cells
CC (PubMed:26766444). {ECO:0000269|PubMed:26766444}.
CC -!- DEVELOPMENTAL STAGE: Expressed from day 7.5 in the primitive streak. At
CC day 9.5, it is expressed in various neural and mesodermal derivatives,
CC mainly along dorsal neural tube, diencephalon, somites and tailbud
CC mesoderm. Strongly expressed in limb buds, particularly in the
CC morphogenetically active region such as the apical ectodermal ridge
CC (AER). {ECO:0000269|PubMed:15469841}.
CC -!- DOMAIN: The FU repeats are required for activation and stabilization of
CC beta-catenin. {ECO:0000269|PubMed:16543246}.
CC -!- DISRUPTION PHENOTYPE: Embryonic lethality due to vascular remodeling
CC defects (PubMed:26766444). Conditional knockout in endothelial cells
CC results in impaired developmental and tumor vascular remodeling. Mice
CC show endothelial cell apoptosis and vascular pruning, leading to
CC reduced microvessel density (PubMed:26766444).
CC {ECO:0000269|PubMed:26766444}.
CC -!- SIMILARITY: Belongs to the R-spondin family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAC36296.1; Type=Frameshift; Evidence={ECO:0000305};
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DR EMBL; AY864332; AAX57441.1; -; mRNA.
DR EMBL; AB055811; BAC41353.1; -; mRNA.
DR EMBL; AK013366; BAB28811.1; -; mRNA.
DR EMBL; AK076308; BAC36296.1; ALT_FRAME; mRNA.
DR EMBL; BC103794; AAI03795.1; -; mRNA.
DR EMBL; BC145929; AAI45930.1; -; mRNA.
DR EMBL; BC145931; AAI45932.1; -; mRNA.
DR CCDS; CCDS23761.1; -.
DR RefSeq; NP_082627.3; NM_028351.3.
DR AlphaFoldDB; Q2TJ95; -.
DR SMR; Q2TJ95; -.
DR STRING; 10090.ENSMUSP00000090287; -.
DR GlyGen; Q2TJ95; 1 site.
DR iPTMnet; Q2TJ95; -.
DR PhosphoSitePlus; Q2TJ95; -.
DR PaxDb; Q2TJ95; -.
DR PRIDE; Q2TJ95; -.
DR ProteomicsDB; 260938; -.
DR Antibodypedia; 32746; 236 antibodies from 33 providers.
DR DNASU; 72780; -.
DR Ensembl; ENSMUST00000092623; ENSMUSP00000090287; ENSMUSG00000019880.
DR GeneID; 72780; -.
DR KEGG; mmu:72780; -.
DR UCSC; uc007etb.2; mouse.
DR CTD; 84870; -.
DR MGI; MGI:1920030; Rspo3.
DR VEuPathDB; HostDB:ENSMUSG00000019880; -.
DR eggNOG; KOG3525; Eukaryota.
DR GeneTree; ENSGT00940000157815; -.
DR HOGENOM; CLU_064219_0_0_1; -.
DR InParanoid; Q2TJ95; -.
DR OMA; WFFITLN; -.
DR OrthoDB; 1441603at2759; -.
DR PhylomeDB; Q2TJ95; -.
DR TreeFam; TF331799; -.
DR Reactome; R-MMU-4641263; Regulation of FZD by ubiquitination.
DR BioGRID-ORCS; 72780; 0 hits in 74 CRISPR screens.
DR ChiTaRS; Rspo3; mouse.
DR PRO; PR:Q2TJ95; -.
DR Proteomes; UP000000589; Chromosome 10.
DR RNAct; Q2TJ95; protein.
DR Bgee; ENSMUSG00000019880; Expressed in vas deferens and 242 other tissues.
DR ExpressionAtlas; Q2TJ95; baseline and differential.
DR Genevisible; Q2TJ95; MM.
DR GO; GO:0005576; C:extracellular region; IDA:MGI.
DR GO; GO:0005109; F:frizzled binding; IPI:MGI.
DR GO; GO:0008201; F:heparin binding; IDA:MGI.
DR GO; GO:0005102; F:signaling receptor binding; IPI:MGI.
DR GO; GO:0001525; P:angiogenesis; IMP:MGI.
DR GO; GO:0001974; P:blood vessel remodeling; IMP:UniProtKB.
DR GO; GO:0060670; P:branching involved in labyrinthine layer morphogenesis; IMP:MGI.
DR GO; GO:0060070; P:canonical Wnt signaling pathway; IMP:MGI.
DR GO; GO:0060173; P:limb development; ISS:UniProtKB.
DR GO; GO:0090263; P:positive regulation of canonical Wnt signaling pathway; IDA:MGI.
DR GO; GO:2000052; P:positive regulation of non-canonical Wnt signaling pathway; IMP:UniProtKB.
DR GO; GO:0030177; P:positive regulation of Wnt signaling pathway; ISO:MGI.
DR GO; GO:0002040; P:sprouting angiogenesis; IMP:UniProtKB.
DR CDD; cd00064; FU; 1.
DR Gene3D; 2.20.100.10; -; 1.
DR InterPro; IPR006212; Furin_repeat.
DR InterPro; IPR009030; Growth_fac_rcpt_cys_sf.
DR InterPro; IPR042994; RSPO3.
DR InterPro; IPR043601; Rspo_Fu-CRD_dom.
DR InterPro; IPR000884; TSP1_rpt.
DR InterPro; IPR036383; TSP1_rpt_sf.
DR PANTHER; PTHR46987:SF1; PTHR46987:SF1; 2.
DR Pfam; PF15913; Furin-like_2; 1.
DR SMART; SM00261; FU; 2.
DR SMART; SM00209; TSP1; 1.
DR SUPFAM; SSF57184; SSF57184; 1.
DR SUPFAM; SSF82895; SSF82895; 1.
DR PROSITE; PS50092; TSP1; 1.
PE 1: Evidence at protein level;
KW Disulfide bond; Glycoprotein; Heparin-binding; Reference proteome; Repeat;
KW Secreted; Sensory transduction; Signal; Wnt signaling pathway.
FT SIGNAL 1..21
FT /evidence="ECO:0000255"
FT CHAIN 22..277
FT /note="R-spondin-3"
FT /id="PRO_0000234444"
FT REPEAT 35..86
FT /note="FU 1"
FT REPEAT 92..135
FT /note="FU 2"
FT DOMAIN 147..207
FT /note="TSP type-1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00210"
FT REGION 210..277
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 247..268
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT CARBOHYD 36
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 41..48
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00210"
FT DISULFID 45..54
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00210"
FT DISULFID 57..76
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00210"
FT DISULFID 80..95
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00210"
FT DISULFID 98..105
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00210"
FT DISULFID 102..111
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00210"
FT DISULFID 114..125
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00210"
FT DISULFID 129..142
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00210"
FT DISULFID 148..190
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00210"
FT DISULFID 159..166
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00210"
FT DISULFID 199..206
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00210"
FT CONFLICT 108
FT /note="K -> Q (in Ref. 1; AAX57441 and 3; BAC36296)"
FT /evidence="ECO:0000305"
FT CONFLICT 130
FT /note="P -> A (in Ref. 2; BAC41353)"
FT /evidence="ECO:0000305"
FT CONFLICT 170
FT /note="R -> G (in Ref. 3; BAB28811)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 277 AA; 31454 MW; 9C5AD3A48AFF8C66 CRC64;
MHLRLISCFF IILNFMEYIG SQNASRGRRQ RRMHPNVSQG CQGGCATCSD YNGCLSCKPR
LFFVLERIGM KQIGVCLSSC PSGYYGTRYP DINKCTKCKV DCDTCFNKNF CTKCKSGFYL
HLGKCLDSCP EGLEANNHTM ECVSIVHCEA SEWSPWSPCM KKGKTCGFKR GTETRVRDIL
QHPSAKGNLC PPTSETRTCI VQRKKCSKGE RGKKGRERKR KKLNKEERKE TSSSSDSKGL
ESSIETPDQQ ENKERQQQQK RRARDKQQKS VSVSTVH
