SCUB2_MOUSE
ID SCUB2_MOUSE Reviewed; 997 AA.
AC Q9JJS0;
DT 31-OCT-2006, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-2000, sequence version 1.
DT 03-AUG-2022, entry version 144.
DE RecName: Full=Signal peptide, CUB and EGF-like domain-containing protein 2 {ECO:0000250|UniProtKB:Q9NQ36};
DE AltName: Full=Protein CEGP1;
DE AltName: Full=Scube/You {ECO:0000303|PubMed:22677548};
DE Flags: Precursor;
GN Name=Scube2 {ECO:0000312|MGI:MGI:1928765}; Synonyms=Cegp1;
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 [GENOMIC DNA].
RX PubMed=11528127; DOI=10.1159/000056999;
RA Amid C., Bahr A., Mujica A., Sampson N., Bikar S.E., Winterpacht A.,
RA Zabel B., Hankeln T., Schmidt E.R.;
RT "Comparative genomic sequencing reveals a strikingly similar architecture
RT of a conserved syntenic region on human chromosome 11p15.3 (including gene
RT ST5) and mouse chromosome 7.";
RL Cytogenet. Cell Genet. 93:284-290(2001).
RN [2]
RP TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE.
RX PubMed=11287194; DOI=10.1016/s0925-4773(00)00586-4;
RA Grimmond S., Larder R., Van Hateren N., Siggers P., Morse S., Hacker T.,
RA Arkell R., Greenfield A.;
RT "Expression of a novel mammalian epidermal growth factor-related gene
RT during mouse neural development.";
RL Mech. Dev. 102:209-211(2001).
RN [3]
RP FUNCTION, INTERACTION WITH SHH, AND SUBUNIT.
RX PubMed=22677548; DOI=10.1101/gad.191866.112;
RA Creanga A., Glenn T.D., Mann R.K., Saunders A.M., Talbot W.S., Beachy P.A.;
RT "Scube/You activity mediates release of dually lipid-modified Hedgehog
RT signal in soluble form.";
RL Genes Dev. 26:1312-1325(2012).
RN [4]
RP MUTAGENESIS OF 845-ILE--ILE-854, FUNCTION, INTERACTION WITH SHH, AND
RP SUBUNIT.
RX PubMed=22902404; DOI=10.1016/j.celrep.2012.07.010;
RA Tukachinsky H., Kuzmickas R.P., Jao C.Y., Liu J., Salic A.;
RT "Dispatched and scube mediate the efficient secretion of the cholesterol-
RT modified hedgehog ligand.";
RL Cell Rep. 2:308-320(2012).
RN [5]
RP INTERACTION WITH SHH, FUNCTION, SUBUNIT, AND DOMAIN.
RX PubMed=24522195; DOI=10.1242/jcs.137695;
RA Jakobs P., Exner S., Schuermann S., Pickhinke U., Bandari S., Ortmann C.,
RA Kupich S., Schulz P., Hansen U., Seidler D.G., Grobe K.;
RT "Scube2 enhances proteolytic Shh processing from the surface of Shh-
RT producing cells.";
RL J. Cell Sci. 127:1726-1737(2014).
RN [6]
RP REVIEW, AND FUNCTION.
RX PubMed=26875496; DOI=10.1016/j.ydbio.2016.02.009;
RA Xavier G.M., Seppala M., Barrell W., Birjandi A.A., Geoghegan F.,
RA Cobourne M.T.;
RT "Hedgehog receptor function during craniofacial development.";
RL Dev. Biol. 415:198-215(2016).
RN [7]
RP DISRUPTION PHENOTYPE, FUNCTION, INTERACTION WITH VEGFR2, AND SUBUNIT.
RX PubMed=27834687; DOI=10.1161/atvbaha.116.308546;
RA Lin Y.C., Chao T.Y., Yeh C.T., Roffler S.R., Kannagi R., Yang R.B.;
RT "Endothelial SCUBE2 interacts with VEGFR2 and regulates VEGF-induced
RT angiogenesis.";
RL Arterioscler. Thromb. Vasc. Biol. 37:144-155(2017).
CC -!- FUNCTION: Lipid-binding protein required for SHH long-range signaling
CC by binding to the dually lipid-modified SHH (ShhNp) and by promoting
CC ShhNp mobilization, solubilization and release from the cell membrane
CC (PubMed:22902404, PubMed:22677548). Acts by enhancing the proteolytic
CC processing (shedding) of the lipid-modified N- and C- terminal of ShhNp
CC at the cell surface (PubMed:24522195). Synergizes with DISP1 to cause
CC an increase in SHH secretion (PubMed:22902404). Probable cell surface
CC coreceptor for VEGFR2 involved in VEGFR2-mediated angiogenesis
CC (PubMed:27834687). {ECO:0000269|PubMed:22677548,
CC ECO:0000269|PubMed:22902404, ECO:0000269|PubMed:24522195,
CC ECO:0000269|PubMed:27834687}.
CC -!- SUBUNIT: Interacts with SHH via the cholesterol anchor of the dually
CC lipid-modified SHH (ShhNp) (PubMed:22902404). Interacts with PTCH1
CC (PubMed:22902404). Forms homooligomers and heterooligomers with SCUBE1
CC and SCUBE3 (By similarity). Interacts with VEGFR2 (PubMed:27834687).
CC {ECO:0000250|UniProtKB:Q8IWY4, ECO:0000250|UniProtKB:Q8IX30,
CC ECO:0000269|PubMed:22902404, ECO:0000269|PubMed:27834687}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250|UniProtKB:Q9NQ36}. Cell
CC surface {ECO:0000250|UniProtKB:Q9NQ36}. Note=Secreted and tethered at
CC the cell surface. {ECO:0000250|UniProtKB:Q9NQ36}.
CC -!- TISSUE SPECIFICITY: Expressed in adult heart, lung and testis.
CC {ECO:0000269|PubMed:11287194}.
CC -!- DEVELOPMENTAL STAGE: Expressed exclusively in the neurepithelium.
CC {ECO:0000269|PubMed:11287194}.
CC -!- DOMAIN: The CUB domain is important for the interaction with the
CC cholesterol-anchor of SHH. The CUB domain regulates protease
CC recruitment and activation during SHH shedding.
CC {ECO:0000269|PubMed:24522195}.
CC -!- PTM: N-glycosylated. {ECO:0000250|UniProtKB:Q9NQ36}.
CC -!- DISRUPTION PHENOTYPE: Mutant mice with endothelial-specific
CC inactivation of Scube2 show normal vasculogenesis and angiogenesis
CC during embryonic development, but impaired response to exogenous VEGF,
CC and impaired response of the endothelium to revascularization after
CC ischemia induced by femoral artery ligation in adult (PubMed:27834687).
CC {ECO:0000269|PubMed:27834687}.
CC -!- CAUTION: It is unclear how SCUBE2 binds the dilipidated SHH. According
CC to a report, the SHH cholesterol-anchor, but not palmitate, seems to be
CC both necessary and sufficient for SCUBE2-mediated SHH release from the
CC cell membrane (PubMed:22902404). According to a second report, SHH
CC palmitoylation accelerates the rate of SCUBE2-mediated release
CC (PubMed:22677548). Cholesterol modification is sufficient for a
CC heterologous protein to bind to SCUBE2 and to be secreted in a SCUBE2-
CC dependent manner (PubMed:22902404). {ECO:0000269|PubMed:22677548,
CC ECO:0000269|PubMed:22902404}.
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; AJ400878; CAB92293.1; -; Genomic_DNA.
DR AlphaFoldDB; Q9JJS0; -.
DR STRING; 10090.ENSMUSP00000007423; -.
DR GlyGen; Q9JJS0; 1 site.
DR iPTMnet; Q9JJS0; -.
DR PhosphoSitePlus; Q9JJS0; -.
DR MaxQB; Q9JJS0; -.
DR PRIDE; Q9JJS0; -.
DR ProteomicsDB; 255502; -.
DR Antibodypedia; 1601; 184 antibodies from 27 providers.
DR Ensembl; ENSMUST00000007423; ENSMUSP00000007423; ENSMUSG00000007279.
DR UCSC; uc009jei.2; mouse.
DR MGI; MGI:1928765; Scube2.
DR VEuPathDB; HostDB:ENSMUSG00000007279; -.
DR eggNOG; KOG1217; Eukaryota.
DR GeneTree; ENSGT00940000153185; -.
DR InParanoid; Q9JJS0; -.
DR OMA; GEGRKCE; -.
DR PhylomeDB; Q9JJS0; -.
DR TreeFam; TF351672; -.
DR Reactome; R-MMU-5362798; Release of Hh-Np from the secreting cell.
DR ChiTaRS; Scube2; mouse.
DR PRO; PR:Q9JJS0; -.
DR Proteomes; UP000000589; Chromosome 7.
DR RNAct; Q9JJS0; protein.
DR Bgee; ENSMUSG00000007279; Expressed in interventricular septum and 137 other tissues.
DR ExpressionAtlas; Q9JJS0; baseline and differential.
DR Genevisible; Q9JJS0; MM.
DR GO; GO:0009986; C:cell surface; IBA:GO_Central.
DR GO; GO:0005615; C:extracellular space; IDA:MGI.
DR GO; GO:0019897; C:extrinsic component of plasma membrane; ISO:MGI.
DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
DR GO; GO:0097108; F:hedgehog family protein binding; IPI:MGI.
DR GO; GO:0042802; F:identical protein binding; ISO:MGI.
DR GO; GO:0008289; F:lipid binding; IEA:UniProtKB-KW.
DR GO; GO:0003413; P:chondrocyte differentiation involved in endochondral bone morphogenesis; IMP:MGI.
DR GO; GO:1902732; P:positive regulation of chondrocyte proliferation; IMP:MGI.
DR GO; GO:0045778; P:positive regulation of ossification; IMP:MGI.
DR GO; GO:0045669; P:positive regulation of osteoblast differentiation; IDA:MGI.
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; 1.
DR Pfam; PF07699; Ephrin_rec_like; 3.
DR SMART; SM00042; CUB; 1.
DR SMART; SM00181; EGF; 10.
DR SMART; SM00179; EGF_CA; 7.
DR SUPFAM; SSF49854; SSF49854; 1.
DR SUPFAM; SSF57184; SSF57184; 4.
DR PROSITE; PS00010; ASX_HYDROXYL; 6.
DR PROSITE; PS01180; CUB; 1.
DR PROSITE; PS01186; EGF_2; 8.
DR PROSITE; PS50026; EGF_3; 6.
DR PROSITE; PS01187; EGF_CA; 6.
PE 1: Evidence at protein level;
KW Calcium; Developmental protein; Disulfide bond; EGF-like domain;
KW Glycoprotein; Lipid-binding; Reference proteome; Repeat; Secreted; Signal.
FT SIGNAL 1..28
FT /evidence="ECO:0000255"
FT CHAIN 29..997
FT /note="Signal peptide, CUB and EGF-like domain-containing
FT protein 2"
FT /id="PRO_0000255581"
FT DOMAIN 43..83
FT /note="EGF-like 1; calcium-binding"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 84..125
FT /note="EGF-like 2; calcium-binding"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 126..162
FT /note="EGF-like 3; calcium-binding"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 175..211
FT /note="EGF-like 4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 215..250
FT /note="EGF-like 5"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 284..319
FT /note="EGF-like 6"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 321..361
FT /note="EGF-like 7; calcium-binding"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 362..400
FT /note="EGF-like 8; calcium-binding"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 401..441
FT /note="EGF-like 9; calcium-binding"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 807..919
FT /note="CUB"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00059"
FT REGION 845..854
FT /note="Interaction with the cholesterol-anchor of SHH"
FT /evidence="ECO:0000269|PubMed:22902404"
FT CARBOHYD 657
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 47..60
FT /evidence="ECO:0000250"
FT DISULFID 54..69
FT /evidence="ECO:0000250"
FT DISULFID 71..82
FT /evidence="ECO:0000250"
FT DISULFID 88..100
FT /evidence="ECO:0000250"
FT DISULFID 96..109
FT /evidence="ECO:0000250"
FT DISULFID 111..124
FT /evidence="ECO:0000250"
FT DISULFID 130..141
FT /evidence="ECO:0000250"
FT DISULFID 137..150
FT /evidence="ECO:0000250"
FT DISULFID 325..336
FT /evidence="ECO:0000250"
FT DISULFID 332..345
FT /evidence="ECO:0000250"
FT DISULFID 347..360
FT /evidence="ECO:0000250"
FT DISULFID 366..376
FT /evidence="ECO:0000250"
FT DISULFID 372..385
FT /evidence="ECO:0000250"
FT DISULFID 387..399
FT /evidence="ECO:0000250"
FT DISULFID 405..416
FT /evidence="ECO:0000250"
FT DISULFID 412..425
FT /evidence="ECO:0000250"
FT DISULFID 427..440
FT /evidence="ECO:0000250"
FT DISULFID 807..833
FT /evidence="ECO:0000250"
FT DISULFID 860..881
FT /evidence="ECO:0000250"
FT MUTAGEN 845..854
FT /note="ILIVVPEIFL->AAAAAPEAAA: No interaction with SHH and
FT no secretion of SHH."
FT /evidence="ECO:0000269|PubMed:22902404"
SQ SEQUENCE 997 AA; 109924 MW; E0261CD9C8F70701 CRC64;
MGVAGCGRPR EARALLLLLL LLPPLLAAAV PPDRGLTNGP SEDVDECAQG LDDCHADALC
QNTPTSYKCS CKPGYQGEGR QCEDMDECDN TLNGGCVHDC LNIPGNYRCT CFDGFMLAHD
GHNCLDMDEC LENNGGCQHI CTNVIGSYEC RCKEGFFLSD NQHTCIHRSE EGLSCMNKDH
GCGHICKEAP RGSVACECRP GFELAKNQKD CILTCNHGNG GCQHSCEDTA EGPECSCHPR
YRLHADGRSC LEQEGTVLEG TESNATSVAD GDKRVKRRLL METCAVNNGG CDRTCKDTST
GVHCSCPTGF TLQVDGKTCK DIDECQTRNG GCNHFCKNTV GSFDCSCKKG FKLLTDEKSC
QDVDECSLER TCDHSCINHP GTFICACNPG YTLYSFTHCG DTNECSVNNG GCQQVCINTV
GSYECQCHPG FKLHWNKKDC VEVKGFPPTS MTPRVSLHCG KSGGGDRCFL RCRSGIHLSS
DVVTVRTSVT FKLNEGKCSL QKAKLSPEGL RPALPERHSS VKESFQYANL TCSPGKQVPG
ALGRLNAPKE MFITVEFERE TYEKEVTASC NLSCVVKRTE KRLRKALRTL KRAAHREQFH
LQLSGMDLDM AKTPSRVSGQ HEETCGVGQG HEESQCVSCR AGTYYDGSQE RCILCPNGTF
QNEEGQVTCE PCPRPENLGS LKISEAWNVS DCGGLCQPGE YSANGFAPCQ LCALGTFQPD
VGRTSCLSCG GGLPTKHLGA TSFQDCETRV QCSPGHFYNT TTHRCIRCPL GTYQPEFGKN
NCVSCPGNTT TDFDGSTNIT QCKNRKCGGE LGDFTGYIES PNYPGNYPAN SECTWTINPP
PKRRILIVVP EIFLPIEDDC GDYLVMRKTS SSNSVTTYET CQTYERPIAF TSRSKKLWIQ
FKSNEGNSAR GFQVPYVTYD EDYQELIEDI VRDGRLYASE NHQEILKDKK LIKALFDVLA
HPQNYFKYTA QESREMFPRS FIRLLRSKVS RFLRPYK
