RSPO4_HUMAN
ID RSPO4_HUMAN Reviewed; 234 AA.
AC Q2I0M5; A2A2I6; Q9UGB2;
DT 16-MAY-2006, integrated into UniProtKB/Swiss-Prot.
DT 16-MAY-2006, sequence version 2.
DT 03-AUG-2022, entry version 137.
DE RecName: Full=R-spondin-4;
DE AltName: Full=Roof plate-specific spondin-4;
DE Short=hRspo4;
DE Flags: Precursor;
GN Name=RSPO4; Synonyms=C20orf182;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RX PubMed=16357527; DOI=10.4161/cc.5.1.2305;
RA Kim K.-A., Zhao J., Andarmani S., Kakitani M., Oshima T., Binnerts M.E.,
RA Abo A., Tomizuka K., Funk W.D.;
RT "R-spondin proteins: a novel link to beta-catenin activation.";
RL Cell Cycle 5:23-26(2006).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Glial tumor;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=11780052; DOI=10.1038/414865a;
RA Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R.,
RA Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L.,
RA Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M., Beasley O.P.,
RA Bird C.P., Blakey S.E., Bridgeman A.M., Brown A.J., Buck D., Burrill W.D.,
RA Butler A.P., Carder C., Carter N.P., Chapman J.C., Clamp M., Clark G.,
RA Clark L.N., Clark S.Y., Clee C.M., Clegg S., Cobley V.E., Collier R.E.,
RA Connor R.E., Corby N.R., Coulson A., Coville G.J., Deadman R., Dhami P.D.,
RA Dunn M., Ellington A.G., Frankland J.A., Fraser A., French L., Garner P.,
RA Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E.,
RA Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J.,
RA Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D.,
RA Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S.,
RA Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D.,
RA Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A.,
RA Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T.,
RA Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I.,
RA Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H., Rice C.M.,
RA Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., Skuce C.D.,
RA Smith M.L., Soderlund C., Steward C.A., Sulston J.E., Swann R.M.,
RA Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., Tracey A.,
RA Tromans A.C., Vaudin M., Wall M., Wallis J.M., Whitehead S.L.,
RA Whittaker P., Willey D.L., Williams L., Williams S.A., Wilming L.,
RA Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 20.";
RL Nature 414:865-871(2001).
RN [4]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=15144186; DOI=10.1021/ac035352d;
RA Brill L.M., Salomon A.R., Ficarro S.B., Mukherji M., Stettler-Gill M.,
RA Peters E.C.;
RT "Robust phosphoproteomic profiling of tyrosine phosphorylation sites from
RT human T cells using immobilized metal affinity chromatography and tandem
RT mass spectrometry.";
RL Anal. Chem. 76:2763-2772(2004).
RN [5]
RP FUNCTION, AND INTERACTION WITH LGR4 AND LGR5.
RX PubMed=21909076; DOI=10.1038/embor.2011.175;
RA Glinka A., Dolde C., Kirsch N., Huang Y.L., Kazanskaya O., Ingelfinger D.,
RA Boutros M., Cruciat C.M., Niehrs C.;
RT "LGR4 and LGR5 are R-spondin receptors mediating Wnt/beta-catenin and
RT Wnt/PCP signalling.";
RL EMBO Rep. 12:1055-1061(2011).
RN [6]
RP FUNCTION, AND INTERACTION WITH LGR4; LGR5 AND LGR6.
RX PubMed=21727895; DOI=10.1038/nature10337;
RA de Lau W., Barker N., Low T.Y., Koo B.K., Li V.S., Teunissen H., Kujala P.,
RA Haegebarth A., Peters P.J., van de Wetering M., Stange D.E., van Es J.E.,
RA Guardavaccaro D., Schasfoort R.B., Mohri Y., Nishimori K., Mohammed S.,
RA Heck A.J., Clevers H.;
RT "Lgr5 homologues associate with Wnt receptors and mediate R-spondin
RT signalling.";
RL Nature 476:293-297(2011).
RN [7]
RP FUNCTION.
RX PubMed=29769720; DOI=10.1038/s41586-018-0118-y;
RA Szenker-Ravi E., Altunoglu U., Leushacke M., Bosso-Lefevre C., Khatoo M.,
RA Thi Tran H., Naert T., Noelanders R., Hajamohideen A., Beneteau C.,
RA de Sousa S.B., Karaman B., Latypova X., Basaran S., Yuecel E.B., Tan T.T.,
RA Vlaminck L., Nayak S.S., Shukla A., Girisha K.M., Le Caignec C.,
RA Soshnikova N., Uyguner Z.O., Vleminckx K., Barker N., Kayserili H.,
RA Reversade B.;
RT "RSPO2 inhibition of RNF43 and ZNRF3 governs limb development independently
RT of LGR4/5/6.";
RL Nature 557:564-569(2018).
RN [8]
RP VARIANTS NDNC4 ARG-65; PHE-95; ARG-107 AND TYR-118.
RX PubMed=17041604; DOI=10.1038/ng1883;
RA Blaydon D.C., Ishii Y., O'Toole E.A., Unsworth H.C., Teh M.-T.,
RA Rueschendorf F., Sinclair C., Hopsu-Havu V.K., Tidman N., Moss C.,
RA Watson R., de Berker D., Wajid M., Christiano A.M., Kelsell D.P.;
RT "The gene encoding R-spondin 4 (RSPO4), a secreted protein implicated in
RT Wnt signaling, is mutated in inherited anonychia.";
RL Nat. Genet. 38:1245-1247(2006).
CC -!- FUNCTION: Activator of the canonical Wnt signaling pathway by acting as
CC a ligand for LGR4-6 receptors (PubMed:29769720). Upon binding to LGR4-6
CC (LGR4, LGR5 or LGR6), LGR4-6 associate with phosphorylated LRP6 and
CC frizzled receptors that are activated by extracellular Wnt receptors,
CC triggering the canonical Wnt signaling pathway to increase expression
CC of target genes. Also regulates the canonical Wnt/beta-catenin-
CC dependent pathway and non-canonical Wnt signaling by acting as an
CC inhibitor of ZNRF3, an important regulator of the Wnt signaling pathway
CC (PubMed:21727895, PubMed:21909076). {ECO:0000269|PubMed:21727895,
CC ECO:0000269|PubMed:21909076, ECO:0000269|PubMed:29769720}.
CC -!- SUBUNIT: Binds heparin (By similarity). Interacts with LGR4, LGR5 and
CC LGR6. {ECO:0000250, ECO:0000269|PubMed:21727895,
CC ECO:0000269|PubMed:21909076}.
CC -!- INTERACTION:
CC Q2I0M5; X5D778: ANKRD11; NbExp=3; IntAct=EBI-12821217, EBI-17183751;
CC Q2I0M5; Q6P158: DHX57; NbExp=3; IntAct=EBI-12821217, EBI-1051531;
CC Q2I0M5; Q9P2W3: GNG13; NbExp=3; IntAct=EBI-12821217, EBI-11427343;
CC Q2I0M5; Q9Y4H4: GPSM3; NbExp=3; IntAct=EBI-12821217, EBI-347538;
CC Q2I0M5; Q96NT3-2: GUCD1; NbExp=3; IntAct=EBI-12821217, EBI-11978177;
CC Q2I0M5; O14964: HGS; NbExp=3; IntAct=EBI-12821217, EBI-740220;
CC Q2I0M5; Q2WGJ6: KLHL38; NbExp=3; IntAct=EBI-12821217, EBI-6426443;
CC Q2I0M5; P45984: MAPK9; NbExp=3; IntAct=EBI-12821217, EBI-713568;
CC Q2I0M5; Q13064: MKRN3; NbExp=3; IntAct=EBI-12821217, EBI-2340269;
CC Q2I0M5; Q8WWB5: PIH1D2; NbExp=3; IntAct=EBI-12821217, EBI-10232538;
CC Q2I0M5; O75716: STK16; NbExp=3; IntAct=EBI-12821217, EBI-749295;
CC Q2I0M5; A0A024R8A9: USP20; NbExp=3; IntAct=EBI-12821217, EBI-14096082;
CC Q2I0M5; Q9Y3S2: ZNF330; NbExp=3; IntAct=EBI-12821217, EBI-373456;
CC Q2I0M5; Q15935: ZNF77; NbExp=3; IntAct=EBI-12821217, EBI-12840750;
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q2I0M5-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q2I0M5-2; Sequence=VSP_018325;
CC -!- DOMAIN: The FU repeat is required for activation and stabilization of
CC beta-catenin. {ECO:0000250}.
CC -!- PTM: Tyr-112 may be phosphorylated; however as this position is
CC probably extracellular, the vivo relevance is not proven.
CC -!- DISEASE: Nail disorder, non-syndromic congenital, 4 (NDNC4)
CC [MIM:206800]: A nail disorder characterized by congenital anonychia or
CC its milder phenotypic variant hyponychia. Anonychia/hyponychia is the
CC absence or severe hypoplasia of all fingernails and toenails without
CC significant bone anomalies. {ECO:0000269|PubMed:17041604}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the R-spondin family. {ECO:0000305}.
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DR EMBL; DQ355152; ABC75877.1; -; mRNA.
DR EMBL; AK122609; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; AL050325; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR CCDS; CCDS42845.1; -. [Q2I0M5-2]
DR CCDS; CCDS42846.1; -. [Q2I0M5-1]
DR RefSeq; NP_001025042.2; NM_001029871.3. [Q2I0M5-1]
DR RefSeq; NP_001035096.1; NM_001040007.2. [Q2I0M5-2]
DR AlphaFoldDB; Q2I0M5; -.
DR SMR; Q2I0M5; -.
DR BioGRID; 131268; 15.
DR IntAct; Q2I0M5; 14.
DR STRING; 9606.ENSP00000217260; -.
DR GlyGen; Q2I0M5; 1 site.
DR iPTMnet; Q2I0M5; -.
DR PhosphoSitePlus; Q2I0M5; -.
DR BioMuta; RSPO4; -.
DR DMDM; 97189858; -.
DR MassIVE; Q2I0M5; -.
DR PaxDb; Q2I0M5; -.
DR PeptideAtlas; Q2I0M5; -.
DR PRIDE; Q2I0M5; -.
DR ProteomicsDB; 61298; -. [Q2I0M5-1]
DR ProteomicsDB; 61299; -. [Q2I0M5-2]
DR Antibodypedia; 54131; 79 antibodies from 19 providers.
DR DNASU; 343637; -.
DR Ensembl; ENST00000217260.9; ENSP00000217260.4; ENSG00000101282.9. [Q2I0M5-1]
DR Ensembl; ENST00000400634.2; ENSP00000383475.2; ENSG00000101282.9. [Q2I0M5-2]
DR GeneID; 343637; -.
DR KEGG; hsa:343637; -.
DR MANE-Select; ENST00000217260.9; ENSP00000217260.4; NM_001029871.4; NP_001025042.2.
DR UCSC; uc002wej.4; human. [Q2I0M5-1]
DR CTD; 343637; -.
DR DisGeNET; 343637; -.
DR GeneCards; RSPO4; -.
DR HGNC; HGNC:16175; RSPO4.
DR HPA; ENSG00000101282; Tissue enhanced (brain, lung).
DR MalaCards; RSPO4; -.
DR MIM; 206800; phenotype.
DR MIM; 610573; gene.
DR neXtProt; NX_Q2I0M5; -.
DR OpenTargets; ENSG00000101282; -.
DR Orphanet; 94150; Anonychia congenita totalis.
DR PharmGKB; PA25726; -.
DR VEuPathDB; HostDB:ENSG00000101282; -.
DR eggNOG; KOG3525; Eukaryota.
DR GeneTree; ENSGT00940000160937; -.
DR HOGENOM; CLU_064219_1_1_1; -.
DR InParanoid; Q2I0M5; -.
DR OMA; NTRECQG; -.
DR OrthoDB; 1441603at2759; -.
DR PhylomeDB; Q2I0M5; -.
DR TreeFam; TF331799; -.
DR PathwayCommons; Q2I0M5; -.
DR Reactome; R-HSA-4641263; Regulation of FZD by ubiquitination.
DR SignaLink; Q2I0M5; -.
DR BioGRID-ORCS; 343637; 12 hits in 1065 CRISPR screens.
DR GenomeRNAi; 343637; -.
DR Pharos; Q2I0M5; Tbio.
DR PRO; PR:Q2I0M5; -.
DR Proteomes; UP000005640; Chromosome 20.
DR RNAct; Q2I0M5; protein.
DR Bgee; ENSG00000101282; Expressed in upper lobe of left lung and 88 other tissues.
DR Genevisible; Q2I0M5; HS.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0008201; F:heparin binding; IEA:UniProtKB-KW.
DR GO; GO:0035878; P:nail development; IMP:MGI.
DR GO; GO:0030177; P:positive regulation of Wnt signaling pathway; IDA:UniProtKB.
DR GO; GO:0016055; P:Wnt signaling pathway; IEA:UniProtKB-KW.
DR CDD; cd00064; FU; 1.
DR InterPro; IPR006212; Furin_repeat.
DR InterPro; IPR009030; Growth_fac_rcpt_cys_sf.
DR InterPro; IPR042993; RSPO2/4.
DR InterPro; IPR043601; Rspo_Fu-CRD_dom.
DR InterPro; IPR000884; TSP1_rpt.
DR PANTHER; PTHR46987:SF4; PTHR46987:SF4; 1.
DR Pfam; PF15913; Furin-like_2; 1.
DR SMART; SM00261; FU; 2.
DR SMART; SM00209; TSP1; 1.
DR SUPFAM; SSF57184; SSF57184; 1.
DR PROSITE; PS50092; TSP1; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Disease variant; Disulfide bond; Glycoprotein;
KW Heparin-binding; Phosphoprotein; Reference proteome; Secreted;
KW Sensory transduction; Signal; Wnt signaling pathway.
FT SIGNAL 1..19
FT /evidence="ECO:0000255"
FT CHAIN 20..234
FT /note="R-spondin-4"
FT /id="PRO_0000234446"
FT REPEAT 85..128
FT /note="FU"
FT DOMAIN 138..197
FT /note="TSP type-1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00210"
FT REGION 190..234
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT CARBOHYD 34
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 35..41
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00210"
FT DISULFID 38..47
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00210"
FT DISULFID 50..69
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00210"
FT DISULFID 73..88
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00210"
FT DISULFID 91..98
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00210"
FT DISULFID 95..104
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00210"
FT DISULFID 107..118
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00210"
FT DISULFID 122..135
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00210"
FT DISULFID 139..181
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00210"
FT DISULFID 150..157
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00210"
FT DISULFID 190..196
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00210"
FT VAR_SEQ 137..198
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:16357527"
FT /id="VSP_018325"
FT VARIANT 65
FT /note="Q -> R (in NDNC4; dbSNP:rs74315420)"
FT /evidence="ECO:0000269|PubMed:17041604"
FT /id="VAR_030399"
FT VARIANT 95
FT /note="C -> F (in NDNC4; dbSNP:rs780506366)"
FT /evidence="ECO:0000269|PubMed:17041604"
FT /id="VAR_030400"
FT VARIANT 106
FT /note="R -> Q (in dbSNP:rs6140807)"
FT /id="VAR_052665"
FT VARIANT 107
FT /note="C -> R (in NDNC4; dbSNP:rs74315421)"
FT /evidence="ECO:0000269|PubMed:17041604"
FT /id="VAR_030401"
FT VARIANT 118
FT /note="C -> Y (in NDNC4; dbSNP:rs74315422)"
FT /evidence="ECO:0000269|PubMed:17041604"
FT /id="VAR_030402"
SQ SEQUENCE 234 AA; 26171 MW; 853E4494533B73F7 CRC64;
MRAPLCLLLL VAHAVDMLAL NRRKKQVGTG LGGNCTGCII CSEENGCSTC QQRLFLFIRR
EGIRQYGKCL HDCPPGYFGI RGQEVNRCKK CGATCESCFS QDFCIRCKRQ FYLYKGKCLP
TCPPGTLAHQ NTRECQGECE LGPWGGWSPC THNGKTCGSA WGLESRVREA GRAGHEEAAT
CQVLSESRKC PIQRPCPGER SPGQKKGRKD RRPRKDRKLD RRLDVRPRQP GLQP
