BTC_HUMAN
ID BTC_HUMAN Reviewed; 178 AA.
AC P35070; Q96F48;
DT 01-FEB-1994, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1994, sequence version 1.
DT 03-AUG-2022, entry version 186.
DE RecName: Full=Probetacellulin;
DE Contains:
DE RecName: Full=Betacellulin;
DE Short=BTC;
DE Flags: Precursor;
GN Name=BTC;
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].
RC TISSUE=Mammary gland;
RX PubMed=8439318; DOI=10.1006/bbrc.1993.1173;
RA Sasada R., Ono Y., Taniyama Y., Shing Y., Folkman J., Igarashi K.;
RT "Cloning and expression of cDNA encoding human betacellulin, a new member
RT of the EGF family.";
RL Biochem. Biophys. Res. Commun. 190:1173-1179(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT MET-124.
RC TISSUE=Ovary;
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 [3]
RP IDENTIFICATION AS EGFR LIGAND.
RX PubMed=8144591; DOI=10.1016/s0021-9258(17)36977-6;
RA Watanabe T., Shintani A., Nakata M., Shing Y., Folkman J., Igarashi K.,
RA Sasada R.;
RT "Recombinant human betacellulin. Molecular structure, biological
RT activities, and receptor interaction.";
RL J. Biol. Chem. 269:9966-9973(1994).
RN [4]
RP TISSUE SPECIFICITY.
RX PubMed=8919026; DOI=10.3109/08977199609003220;
RA Seno M., Tada H., Kosaka M., Sasada R., Igarashi K., Shing Y., Folkman J.,
RA Ueda M., Yamada H.;
RT "Human betacellulin, a member of the EGF family dominantly expressed in
RT pancreas and small intestine, is fully active in a monomeric form.";
RL Growth Factors 13:181-191(1996).
RN [5]
RP FUNCTION, AND INTERACTION WITH EGFR AND ERBB4.
RX PubMed=8570211;
RA Riese D.J. II, Bermingham Y., van Raaij T.M., Buckley S., Plowman G.D.,
RA Stern D.F.;
RT "Betacellulin activates the epidermal growth factor receptor and erbB-4,
RT and induces cellular response patterns distinct from those stimulated by
RT epidermal growth factor or neuregulin-beta.";
RL Oncogene 12:345-353(1996).
RN [6]
RP INTERACTION WITH ERBB4.
RX PubMed=10867024; DOI=10.1074/jbc.c901015199;
RA Sweeney C., Lai C., Riese D.J. II, Diamonti A.J., Cantley L.C.,
RA Carraway K.L. III;
RT "Ligand discrimination in signaling through an ErbB4 receptor homodimer.";
RL J. Biol. Chem. 275:19803-19807(2000).
RN [7]
RP STRUCTURE BY NMR OF 62-111.
RX PubMed=12074582; DOI=10.1016/s0006-291x(02)00585-5;
RA Miura K., Doura H., Aizawa T., Tada H., Seno M., Yamada H., Kawano K.;
RT "Solution structure of betacellulin, a new member of EGF-family ligands.";
RL Biochem. Biophys. Res. Commun. 294:1040-1046(2002).
CC -!- FUNCTION: Growth factor that binds to EGFR, ERBB4 and other EGF
CC receptor family members. Potent mitogen for retinal pigment epithelial
CC cells and vascular smooth muscle cells. {ECO:0000269|PubMed:8570211}.
CC -!- SUBUNIT: Monomer. Interacts with EGFR and ERBB4.
CC {ECO:0000269|PubMed:10867024, ECO:0000269|PubMed:8570211}.
CC -!- INTERACTION:
CC P35070; Q96IJ6: GMPPA; NbExp=6; IntAct=EBI-6590057, EBI-750953;
CC P35070; Q5T749: KPRP; NbExp=3; IntAct=EBI-6590057, EBI-10981970;
CC P35070; Q15323: KRT31; NbExp=6; IntAct=EBI-6590057, EBI-948001;
CC P35070; Q8IUG1: KRTAP1-3; NbExp=3; IntAct=EBI-6590057, EBI-11749135;
CC P35070; P26447: S100A4; NbExp=2; IntAct=EBI-6590057, EBI-717058;
CC P35070; O43765: SGTA; NbExp=6; IntAct=EBI-6590057, EBI-347996;
CC P35070; Q96EQ0: SGTB; NbExp=3; IntAct=EBI-6590057, EBI-744081;
CC -!- SUBCELLULAR LOCATION: [Betacellulin]: Secreted, extracellular space.
CC -!- SUBCELLULAR LOCATION: [Probetacellulin]: Cell membrane; Single-pass
CC type I membrane protein.
CC -!- TISSUE SPECIFICITY: Synthesized in several tissues and tumor cells.
CC Predominantly expressed in pancreas and small intestine.
CC {ECO:0000269|PubMed:8919026}.
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DR EMBL; S55606; AAB25452.1; -; mRNA.
DR EMBL; BC011618; AAH11618.1; -; mRNA.
DR CCDS; CCDS3566.1; -.
DR PIR; JC1467; JC1467.
DR RefSeq; NP_001303892.1; NM_001316963.1.
DR RefSeq; NP_001720.1; NM_001729.3.
DR RefSeq; XP_011530513.1; XM_011532211.1.
DR PDB; 1IOX; NMR; -; A=62-111.
DR PDB; 1IP0; NMR; -; A=62-111.
DR PDBsum; 1IOX; -.
DR PDBsum; 1IP0; -.
DR AlphaFoldDB; P35070; -.
DR SMR; P35070; -.
DR BioGRID; 107150; 23.
DR DIP; DIP-5768N; -.
DR IntAct; P35070; 10.
DR MINT; P35070; -.
DR STRING; 9606.ENSP00000379092; -.
DR GlyGen; P35070; 1 site.
DR PhosphoSitePlus; P35070; -.
DR SwissPalm; P35070; -.
DR BioMuta; BTC; -.
DR DMDM; 461653; -.
DR MassIVE; P35070; -.
DR PaxDb; P35070; -.
DR PeptideAtlas; P35070; -.
DR PRIDE; P35070; -.
DR ProteomicsDB; 54977; -.
DR Antibodypedia; 13367; 428 antibodies from 34 providers.
DR DNASU; 685; -.
DR Ensembl; ENST00000395743.8; ENSP00000379092.3; ENSG00000174808.12.
DR GeneID; 685; -.
DR KEGG; hsa:685; -.
DR MANE-Select; ENST00000395743.8; ENSP00000379092.3; NM_001729.4; NP_001720.1.
DR UCSC; uc003hig.3; human.
DR CTD; 685; -.
DR DisGeNET; 685; -.
DR GeneCards; BTC; -.
DR HGNC; HGNC:1121; BTC.
DR HPA; ENSG00000174808; Tissue enhanced (intestine).
DR MIM; 600345; gene.
DR neXtProt; NX_P35070; -.
DR OpenTargets; ENSG00000174808; -.
DR PharmGKB; PA25442; -.
DR VEuPathDB; HostDB:ENSG00000174808; -.
DR eggNOG; ENOG502RZHQ; Eukaryota.
DR GeneTree; ENSGT00940000160508; -.
DR HOGENOM; CLU_112513_1_0_1; -.
DR InParanoid; P35070; -.
DR OMA; QPKRKGH; -.
DR OrthoDB; 1401257at2759; -.
DR PhylomeDB; P35070; -.
DR TreeFam; TF332938; -.
DR PathwayCommons; P35070; -.
DR Reactome; R-HSA-1227986; Signaling by ERBB2.
DR Reactome; R-HSA-1236394; Signaling by ERBB4.
DR Reactome; R-HSA-1250196; SHC1 events in ERBB2 signaling.
DR Reactome; R-HSA-1250342; PI3K events in ERBB4 signaling.
DR Reactome; R-HSA-1250347; SHC1 events in ERBB4 signaling.
DR Reactome; R-HSA-1251985; Nuclear signaling by ERBB4.
DR Reactome; R-HSA-1257604; PIP3 activates AKT signaling.
DR Reactome; R-HSA-177929; Signaling by EGFR.
DR Reactome; R-HSA-179812; GRB2 events in EGFR signaling.
DR Reactome; R-HSA-180292; GAB1 signalosome.
DR Reactome; R-HSA-180336; SHC1 events in EGFR signaling.
DR Reactome; R-HSA-182971; EGFR downregulation.
DR Reactome; R-HSA-1963640; GRB2 events in ERBB2 signaling.
DR Reactome; R-HSA-1963642; PI3K events in ERBB2 signaling.
DR Reactome; R-HSA-212718; EGFR interacts with phospholipase C-gamma.
DR Reactome; R-HSA-2219530; Constitutive Signaling by Aberrant PI3K in Cancer.
DR Reactome; R-HSA-5638303; Inhibition of Signaling by Overexpressed EGFR.
DR Reactome; R-HSA-5673001; RAF/MAP kinase cascade.
DR Reactome; R-HSA-6785631; ERBB2 Regulates Cell Motility.
DR Reactome; R-HSA-6811558; PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.
DR Reactome; R-HSA-8847993; ERBB2 Activates PTK6 Signaling.
DR Reactome; R-HSA-8856825; Cargo recognition for clathrin-mediated endocytosis.
DR Reactome; R-HSA-8856828; Clathrin-mediated endocytosis.
DR Reactome; R-HSA-8863795; Downregulation of ERBB2 signaling.
DR Reactome; R-HSA-9009391; Extra-nuclear estrogen signaling.
DR Reactome; R-HSA-9634638; Estrogen-dependent nuclear events downstream of ESR-membrane signaling.
DR Reactome; R-HSA-9664565; Signaling by ERBB2 KD Mutants.
DR Reactome; R-HSA-9665686; Signaling by ERBB2 TMD/JMD mutants.
DR SignaLink; P35070; -.
DR SIGNOR; P35070; -.
DR BioGRID-ORCS; 685; 14 hits in 1072 CRISPR screens.
DR ChiTaRS; BTC; human.
DR EvolutionaryTrace; P35070; -.
DR GenomeRNAi; 685; -.
DR Pharos; P35070; Tbio.
DR PRO; PR:P35070; -.
DR Proteomes; UP000005640; Chromosome 4.
DR RNAct; P35070; protein.
DR Bgee; ENSG00000174808; Expressed in muscle layer of sigmoid colon and 132 other tissues.
DR ExpressionAtlas; P35070; baseline and differential.
DR Genevisible; P35070; HS.
DR GO; GO:0030669; C:clathrin-coated endocytic vesicle membrane; TAS:Reactome.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IDA:MGI.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005154; F:epidermal growth factor receptor binding; IBA:GO_Central.
DR GO; GO:0008083; F:growth factor activity; IBA:GO_Central.
DR GO; GO:0048018; F:receptor ligand activity; IDA:MGI.
DR GO; GO:0030297; F:transmembrane receptor protein tyrosine kinase activator activity; IDA:MGI.
DR GO; GO:0008283; P:cell population proliferation; IEA:Ensembl.
DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; IBA:GO_Central.
DR GO; GO:1904019; P:epithelial cell apoptotic process; IEA:Ensembl.
DR GO; GO:0038134; P:ERBB2-EGFR signaling pathway; IEA:Ensembl.
DR GO; GO:0038138; P:ERBB4-ERBB4 signaling pathway; IDA:MGI.
DR GO; GO:1904036; P:negative regulation of epithelial cell apoptotic process; IEA:Ensembl.
DR GO; GO:0051781; P:positive regulation of cell division; IEA:UniProtKB-KW.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; IBA:GO_Central.
DR GO; GO:0045741; P:positive regulation of epidermal growth factor-activated receptor activity; IBA:GO_Central.
DR GO; GO:0045840; P:positive regulation of mitotic nuclear division; IBA:GO_Central.
DR InterPro; IPR000742; EGF-like_dom.
DR InterPro; IPR015497; EGF_rcpt_ligand.
DR PANTHER; PTHR10740; PTHR10740; 1.
DR PROSITE; PS00022; EGF_1; 1.
DR PROSITE; PS01186; EGF_2; 1.
DR PROSITE; PS50026; EGF_3; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cell membrane; Disulfide bond; EGF-like domain; Glycoprotein;
KW Growth factor; Membrane; Mitogen; Reference proteome; Secreted; Signal;
KW Transmembrane; Transmembrane helix.
FT SIGNAL 1..31
FT /evidence="ECO:0000250"
FT CHAIN 32..178
FT /note="Probetacellulin"
FT /id="PRO_0000300685"
FT CHAIN 32..111
FT /note="Betacellulin"
FT /id="PRO_0000007490"
FT PROPEP 112..178
FT /note="Removed in mature form"
FT /evidence="ECO:0000250"
FT /id="PRO_0000007491"
FT TOPO_DOM 32..118
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 119..139
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 140..178
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 65..105
FT /note="EGF-like"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT CARBOHYD 34
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 69..82
FT DISULFID 77..93
FT DISULFID 95..104
FT VARIANT 7
FT /note="C -> G (in dbSNP:rs28549760)"
FT /id="VAR_029307"
FT VARIANT 44
FT /note="L -> F (in dbSNP:rs56320257)"
FT /id="VAR_061151"
FT VARIANT 124
FT /note="L -> M (in dbSNP:rs11938093)"
FT /evidence="ECO:0000269|PubMed:15489334"
FT /id="VAR_029308"
FT STRAND 66..68
FT /evidence="ECO:0007829|PDB:1IP0"
FT HELIX 71..73
FT /evidence="ECO:0007829|PDB:1IOX"
FT STRAND 82..85
FT /evidence="ECO:0007829|PDB:1IOX"
FT TURN 86..89
FT /evidence="ECO:0007829|PDB:1IOX"
FT STRAND 90..93
FT /evidence="ECO:0007829|PDB:1IOX"
FT TURN 101..104
FT /evidence="ECO:0007829|PDB:1IOX"
FT STRAND 106..108
FT /evidence="ECO:0007829|PDB:1IP0"
SQ SEQUENCE 178 AA; 19746 MW; 27AC77BD92001F0F CRC64;
MDRAARCSGA SSLPLLLALA LGLVILHCVV ADGNSTRSPE TNGLLCGDPE ENCAATTTQS
KRKGHFSRCP KQYKHYCIKG RCRFVVAEQT PSCVCDEGYI GARCERVDLF YLRGDRGQIL
VICLIAVMVV FIILVIGVCT CCHPLRKRRK RKKKEEEMET LGKDITPINE DIEETNIA
