SCUB3_MOUSE
ID SCUB3_MOUSE Reviewed; 993 AA.
AC Q66PY1; B2KF22; Q68FG9;
DT 03-OCT-2006, integrated into UniProtKB/Swiss-Prot.
DT 11-OCT-2004, sequence version 1.
DT 03-AUG-2022, entry version 132.
DE RecName: Full=Signal peptide, CUB and EGF-like domain-containing protein 3;
DE Flags: Precursor;
GN Name=Scube3 {ECO:0000312|MGI:MGI:3045253};
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] {ECO:0000305, ECO:0000312|EMBL:AAU08348.1}
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, AND
RP GLYCOSYLATION.
RC STRAIN=C57BL/6J {ECO:0000312|EMBL:AAU08348.1};
RX PubMed=15234972; DOI=10.1074/jbc.m405912200;
RA Wu B.-T., Su Y.-H., Tsai M.-T., Wasserman S.M., Topper J.N., Yang R.-B.;
RT "A novel secreted, cell-surface glycoprotein containing multiple epidermal
RT growth factor-like repeats and one CUB domain is highly expressed in
RT primary osteoblasts and bones.";
RL J. Biol. Chem. 279:37485-37490(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [3] {ECO:0000305, ECO:0000312|EMBL:AAH79849.1}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 85-993 (ISOFORM 2).
RC STRAIN=C57BL/6J {ECO:0000312|EMBL:AAH79849.1};
RC TISSUE=Brain {ECO:0000312|EMBL:AAH79849.1};
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 FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=33308444; DOI=10.1016/j.ajhg.2020.11.015;
RG Genomics England Research Consortium;
RA Lin Y.C., Niceta M., Muto V., Vona B., Pagnamenta A.T., Maroofian R.,
RA Beetz C., van Duyvenvoorde H., Dentici M.L., Lauffer P., Vallian S.,
RA Ciolfi A., Pizzi S., Bauer P., Gruening N.M., Bellacchio E.,
RA Del Fattore A., Petrini S., Shaheen R., Tiosano D., Halloun R.,
RA Pode-Shakked B., Albayrak H.M., Isik E., Wit J.M., Dittrich M.,
RA Freire B.L., Bertola D.R., Jorge A.A.L., Barel O., Sabir A.H.,
RA Al Tenaiji A.M.J., Taji S.M., Al-Sannaa N., Al-Abdulwahed H., Digilio M.C.,
RA Irving M., Anikster Y., Bhavani G.S.L., Girisha K.M., Haaf T., Taylor J.C.,
RA Dallapiccola B., Alkuraya F.S., Yang R.B., Tartaglia M.;
RT "SCUBE3 loss-of-function causes a recognizable recessive developmental
RT disorder due to defective bone morphogenetic protein signaling.";
RL Am. J. Hum. Genet. 108:115-133(2021).
CC -!- FUNCTION: Is a positive regulator of the BMP signaling pathway,
CC required for proper chondrogenesis, osteogenesis and skeletal
CC development (PubMed:33308444). It acts as coreceptor for BMP ligands,
CC particularly BMP2 and BMP4, facilitating their interactions with BMP
CC type I receptors (By similarity). It is required for ligand-induced
CC recruitment of BMP receptors to lipid rafts (PubMed:33308444). Binds to
CC TGFBR2 and activates TGFB signaling (By similarity).
CC {ECO:0000250|UniProtKB:Q8IX30, ECO:0000269|PubMed:33308444}.
CC -!- SUBUNIT: Forms homooligomers. Forms heterooligomers with SCUBE1 and
CC SCUBE2. Interacts with TGFBR2 through the CUB domain; this interaction
CC does not affect TGFB1-binding to TGFBR2. Interacts with BMP2, BMP4 and
CC BMP7; the interaction is mediated by the CUB domain. Interacts with
CC BMPR1A, BMPR1B and BMPR2; the interaction with BMPR1A and BMPR1B is
CC BMP2- and BMP4-dependent. {ECO:0000250|UniProtKB:Q8IX30}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250|UniProtKB:Q8IX30}. Cell
CC surface {ECO:0000250|UniProtKB:Q8IX30}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1 {ECO:0000269|PubMed:15234972};
CC IsoId=Q66PY1-1; Sequence=Displayed;
CC Name=2 {ECO:0000269|PubMed:15489334};
CC IsoId=Q66PY1-2; Sequence=VSP_052168, VSP_052169;
CC -!- TISSUE SPECIFICITY: Highly expressed in femur and humerus with little
CC or no expression in non-bone tissues. {ECO:0000269|PubMed:15234972}.
CC -!- PTM: N-glycosylated. {ECO:0000269|PubMed:15234972}.
CC -!- PTM: Proteolytic cleavage produces a CUB-containing C-terminal fragment
CC that retains the ability to bind to TGFBR2. This reaction is catalyzed
CC in vitro by MMP2 and, to a lesser extent, by MMP9 (By similarity).
CC {ECO:0000250}.
CC -!- DISRUPTION PHENOTYPE: Knockout mice are viable and do not show any
CC macroscopically visible abnormality at birth. At day P1, however,
CC knockout mice are shorter than their control littermates, and show
CC misaligned upper/lower incisors and altered craniofacial development.
CC All appendicular (forelimbs and hindlimbs) and axial (skull, vertebral
CC column, and rib cage) skeletal elements are smaller than in control
CC animals. The defective skeletal growth persists up to adulthood.
CC {ECO:0000269|PubMed:33308444}.
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DR EMBL; AY639609; AAU08348.1; -; mRNA.
DR EMBL; CT009658; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC079849; AAH79849.1; -; mRNA.
DR CCDS; CCDS37527.1; -. [Q66PY1-1]
DR RefSeq; NP_001004366.1; NM_001004366.1. [Q66PY1-1]
DR RefSeq; XP_011244779.1; XM_011246477.1.
DR AlphaFoldDB; Q66PY1; -.
DR BioGRID; 234583; 3.
DR STRING; 10090.ENSMUSP00000038366; -.
DR GlyConnect; 2713; 1 N-Linked glycan (1 site).
DR GlyGen; Q66PY1; 5 sites, 1 N-linked glycan (1 site).
DR iPTMnet; Q66PY1; -.
DR PhosphoSitePlus; Q66PY1; -.
DR CPTAC; non-CPTAC-4005; -.
DR MaxQB; Q66PY1; -.
DR PaxDb; Q66PY1; -.
DR PeptideAtlas; Q66PY1; -.
DR PRIDE; Q66PY1; -.
DR ProteomicsDB; 255373; -. [Q66PY1-1]
DR ProteomicsDB; 255374; -. [Q66PY1-2]
DR Antibodypedia; 29465; 184 antibodies from 27 providers.
DR DNASU; 268935; -.
DR Ensembl; ENSMUST00000043503; ENSMUSP00000038366; ENSMUSG00000038677. [Q66PY1-1]
DR Ensembl; ENSMUST00000132670; ENSMUSP00000117490; ENSMUSG00000038677. [Q66PY1-2]
DR GeneID; 268935; -.
DR KEGG; mmu:268935; -.
DR UCSC; uc008bqd.1; mouse. [Q66PY1-1]
DR CTD; 222663; -.
DR MGI; MGI:3045253; Scube3.
DR VEuPathDB; HostDB:ENSMUSG00000038677; -.
DR eggNOG; KOG1217; Eukaryota.
DR GeneTree; ENSGT00940000153185; -.
DR HOGENOM; CLU_013079_0_0_1; -.
DR InParanoid; Q66PY1; -.
DR OMA; HGRLHWN; -.
DR OrthoDB; 73164at2759; -.
DR PhylomeDB; Q66PY1; -.
DR TreeFam; TF351672; -.
DR Reactome; R-MMU-1474228; Degradation of the extracellular matrix.
DR BioGRID-ORCS; 268935; 2 hits in 74 CRISPR screens.
DR PRO; PR:Q66PY1; -.
DR Proteomes; UP000000589; Chromosome 17.
DR RNAct; Q66PY1; protein.
DR Bgee; ENSMUSG00000038677; Expressed in floor plate of midbrain and 146 other tissues.
DR ExpressionAtlas; Q66PY1; baseline and differential.
DR Genevisible; Q66PY1; MM.
DR GO; GO:0009986; C:cell surface; ISS:UniProtKB.
DR GO; GO:0005615; C:extracellular space; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; ISO:MGI.
DR GO; GO:0036122; F:BMP binding; ISO:MGI.
DR GO; GO:0070700; F:BMP receptor binding; ISO:MGI.
DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
DR GO; GO:0042802; F:identical protein binding; ISS:UniProtKB.
DR GO; GO:0030513; P:positive regulation of BMP signaling pathway; ISS:UniProtKB.
DR GO; GO:0045669; P:positive regulation of osteoblast differentiation; IMP:UniProtKB.
DR GO; GO:0045880; P:positive regulation of smoothened signaling pathway; IDA:MGI.
DR GO; GO:0007165; P:signal transduction; IBA:GO_Central.
DR CDD; cd00041; CUB; 1.
DR Gene3D; 2.60.120.290; -; 1.
DR InterPro; IPR026823; cEGF.
DR InterPro; IPR000859; CUB_dom.
DR InterPro; IPR001881; EGF-like_Ca-bd_dom.
DR InterPro; IPR000742; EGF-like_dom.
DR InterPro; IPR000152; EGF-type_Asp/Asn_hydroxyl_site.
DR InterPro; IPR018097; EGF_Ca-bd_CS.
DR InterPro; IPR024731; EGF_dom.
DR InterPro; IPR009030; Growth_fac_rcpt_cys_sf.
DR InterPro; IPR035914; Sperma_CUB_dom_sf.
DR InterPro; IPR011641; Tyr-kin_ephrin_A/B_rcpt-like.
DR Pfam; PF12662; cEGF; 1.
DR Pfam; PF00431; CUB; 1.
DR Pfam; PF12947; EGF_3; 1.
DR Pfam; PF07645; EGF_CA; 2.
DR Pfam; PF07699; Ephrin_rec_like; 3.
DR SMART; SM00042; CUB; 1.
DR SMART; SM00181; EGF; 10.
DR SMART; SM00179; EGF_CA; 8.
DR SUPFAM; SSF49854; SSF49854; 1.
DR SUPFAM; SSF57184; SSF57184; 3.
DR PROSITE; PS00010; ASX_HYDROXYL; 6.
DR PROSITE; PS01180; CUB; 1.
DR PROSITE; PS01186; EGF_2; 7.
DR PROSITE; PS50026; EGF_3; 6.
DR PROSITE; PS01187; EGF_CA; 6.
PE 1: Evidence at protein level;
KW Alternative splicing; Calcium; Disulfide bond; EGF-like domain;
KW Glycoprotein; Reference proteome; Repeat; Secreted; Signal.
FT SIGNAL 1..20
FT /evidence="ECO:0000255"
FT CHAIN 21..993
FT /note="Signal peptide, CUB and EGF-like domain-containing
FT protein 3"
FT /evidence="ECO:0000255"
FT /id="PRO_0000250617"
FT DOMAIN 29..69
FT /note="EGF-like 1; calcium-binding"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 70..111
FT /note="EGF-like 2; calcium-binding"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 112..148
FT /note="EGF-like 3; calcium-binding"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 157..198
FT /note="EGF-like 4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 199..237
FT /note="EGF-like 5"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 238..276
FT /note="EGF-like 6"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 277..317
FT /note="EGF-like 7; calcium-binding"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 318..356
FT /note="EGF-like 8; calcium-binding"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 357..398
FT /note="EGF-like 9; calcium-binding"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 804..916
FT /note="CUB"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00059"
FT CARBOHYD 417
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 464
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 685
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 756
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 785
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 33..46
FT /evidence="ECO:0000255"
FT DISULFID 40..55
FT /evidence="ECO:0000255"
FT DISULFID 57..68
FT /evidence="ECO:0000255"
FT DISULFID 74..86
FT /evidence="ECO:0000255"
FT DISULFID 82..95
FT /evidence="ECO:0000255"
FT DISULFID 97..110
FT /evidence="ECO:0000255"
FT DISULFID 116..127
FT /evidence="ECO:0000255"
FT DISULFID 123..136
FT /evidence="ECO:0000255"
FT DISULFID 161..172
FT /evidence="ECO:0000255"
FT DISULFID 168..182
FT /evidence="ECO:0000255"
FT DISULFID 184..197
FT /evidence="ECO:0000255"
FT DISULFID 201..212
FT /evidence="ECO:0000255"
FT DISULFID 208..221
FT /evidence="ECO:0000255"
FT DISULFID 223..236
FT /evidence="ECO:0000255"
FT DISULFID 240..251
FT /evidence="ECO:0000255"
FT DISULFID 247..260
FT /evidence="ECO:0000255"
FT DISULFID 262..275
FT /evidence="ECO:0000255"
FT DISULFID 281..292
FT /evidence="ECO:0000255"
FT DISULFID 288..301
FT /evidence="ECO:0000255"
FT DISULFID 303..316
FT /evidence="ECO:0000255"
FT DISULFID 322..332
FT /evidence="ECO:0000255"
FT DISULFID 328..341
FT /evidence="ECO:0000255"
FT DISULFID 343..355
FT /evidence="ECO:0000255"
FT DISULFID 361..372
FT /evidence="ECO:0000255"
FT DISULFID 368..381
FT /evidence="ECO:0000255"
FT DISULFID 383..397
FT /evidence="ECO:0000255"
FT DISULFID 804..830
FT /evidence="ECO:0000255"
FT DISULFID 857..878
FT /evidence="ECO:0000255"
FT VAR_SEQ 637..690
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_052168"
FT VAR_SEQ 945..993
FT /note="DKKLIKAFFEVLAHPQNYFKYTEKHKEMLPKSFIKLLRSKVSSFLRPYK ->
FT ASERSLWCGWKWVCTDVQANC (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_052169"
SQ SEQUENCE 993 AA; 108984 MW; E43989ACACCC345F CRC64;
MGSGRVPGLC LLLLLVHARA AQHGKAAQDV DECVEGTDNC HIDAICQNTP RSYKCICKSG
YTGDGKHCKD VDECEREDNA GCVHDCVNIP GNYRCTCYDG FHLAHDGHNC LDVDECAEGN
GGCQQSCVNM MGSYECHCRD GFFLSDNQHT CIQRPEEGMN CMNKNHGCAH ICRETPKGGI
ACECRPGFEL TKNQRDCKLT CNYGNGGCQH TCDDTEQGPR CGCHVKFVLH TDGKTCIETC
AVNNGGCDSK CHDAATGVHC SCPVGFMLQP DRKTCKDIDE CRLNNGGCDH ICRNTVGSFE
CSCKKGYKLL INERSCQDID ECSFDRTCDH MCVNTPGSFQ CLCHRGYLLY GVTHCGDVDE
CSINKGGCRF GCINTPGSYQ CTCPAGQGRL HWNGKDCTEP VKCQSSLGAS KAMLSCNRSG
KKDTCALTCP SRARFLPESE NGFTVSCGTP SPKAAPARVI HSGNSTVSSS CHEAAVLPVK
QRASFKIKDA KCRLHLRNKG KAEEASRILG PGSVPCSDCL VTFIHLKCDS SRKGKGRRAR
TPPGKEVTRL TLELEAEVRA EETTAGCGLP CLRQRMERRL KGSLKMLRKS INQDRFLLRL
AGLDYELAHK PGLGAGDRAE LVEVCRPGQH RAGTKCVSCP QGTYYHGQTE QCVPCPAGTF
QEREGQLSCD LCPGSDAHGP LGATNVTTCA GQCPPGHHSG DGFKPCQPCP RGTYQPEAGR
TLCFPCGGGL TTKHEGAVSF QDCDTKVQCS PGHYYNTSIH RCIRCAVGSY QPDFRQNFCT
RCPGNTSTDF DGSTSVAQCK NRQCGGELGE FTGYIESPNY PGNYPAGVEC VWNINPPPKR
KILIVVPEIF LPSEDECGDV LVMRKNSSPS SITTYETCQT YERPIAFTAR SRKLWINFKT
SEANSARGFQ IPYVTYDEDY EQLVEDIVRD GRLYASENHQ EILKDKKLIK AFFEVLAHPQ
NYFKYTEKHK EMLPKSFIKL LRSKVSSFLR PYK
