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 24-JAN-2024, entry version 144. 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}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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 GlyCosmos; Q2I0M5; 1 site, No reported glycans. DR GlyGen; Q2I0M5; 1 site. DR iPTMnet; Q2I0M5; -. DR PhosphoSitePlus; Q2I0M5; -. DR BioMuta; RSPO4; -. DR DMDM; 97189858; -. DR MassIVE; Q2I0M5; -. DR PaxDb; 9606-ENSP00000217260; -. DR PeptideAtlas; Q2I0M5; -. DR ProteomicsDB; 61298; -. [Q2I0M5-1] DR ProteomicsDB; 61299; -. [Q2I0M5-2] DR Antibodypedia; 54131; 91 antibodies from 20 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 AGR; HGNC:16175; -. 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; ATCDSCF; -. DR OrthoDB; 196918at2759; -. 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; 14 hits in 1143 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 cell types or tissues. 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; IPR043601; Rspo_Fu-CRD_dom. DR InterPro; IPR000884; TSP1_rpt. DR PANTHER; PTHR46987; NEUROHYPOPHYSIAL HORMONES, N-TERMINAL DOMAIN CONTAINING PROTEIN; 1. DR PANTHER; PTHR46987:SF6; R-SPONDIN-4; 1. DR Pfam; PF15913; Furin-like_2; 1. DR SMART; SM00261; FU; 2. DR SMART; SM00209; TSP1; 1. DR SUPFAM; SSF57184; Growth factor receptor domain; 1. DR PROSITE; PS50092; TSP1; 1. DR Genevisible; Q2I0M5; HS. 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 //