ID   BMP6_MOUSE              Reviewed;         510 AA.
AC   P20722; B2RRV6;
DT   01-FEB-1991, integrated into UniProtKB/Swiss-Prot.
DT   01-OCT-1996, sequence version 2.
DT   24-JAN-2024, entry version 183.
DE   RecName: Full=Bone morphogenetic protein 6;
DE            Short=BMP-6;
DE   AltName: Full=VG-1-related protein;
DE            Short=VGR-1;
DE   Flags: Precursor;
GN   Name=Bmp6; Synonyms=Bmp-6, Vgr1;
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 [MRNA].
RC   TISSUE=Embryo;
RX   PubMed=8089189; DOI=10.1083/jcb.126.6.1595;
RA   Gitelman S.E., Kobrin M.S., Ye J.Q., Lopez A.R., Lee A., Derynck R.;
RT   "Recombinant Vgr-1/BMP-6-expressing tumors induce fibrosis and endochondral
RT   bone formation in vivo.";
RL   J. Cell Biol. 126:1595-1609(1994).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   PubMed=9069123; DOI=10.1007/s003359900391;
RA   Gitelman S.E., Kobrin M.S., Lee A., Fet V., Lyons K., Hogan B.L.M.,
RA   Derynck R.;
RT   "Structure and sequence of the mouse Bmp6 gene.";
RL   Mamm. Genome 8:212-214(1997).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Brain;
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   NUCLEOTIDE SEQUENCE [MRNA] OF 73-510.
RX   PubMed=2734307; DOI=10.1073/pnas.86.12.4554;
RA   Lyons K., Graycar J.L., Lee A., Hashmi S., Lindquist P.B., Chen E.Y.,
RA   Hogan B.L.M., Derynck R.;
RT   "Vgr-1, a mammalian gene related to Xenopus Vg-1, is a member of the
RT   transforming growth factor beta gene superfamily.";
RL   Proc. Natl. Acad. Sci. U.S.A. 86:4554-4558(1989).
RN   [5]
RP   DISRUPTION PHENOTYPE.
RX   PubMed=9664685;
RX   DOI=10.1002/(sici)1520-6408(1998)22:4<321::aid-dvg3>3.0.co;2-8;
RA   Solloway M.J., Dudley A.T., Bikoff E.K., Lyons K.M., Hogan B.L.,
RA   Robertson E.J.;
RT   "Mice lacking Bmp6 function.";
RL   Dev. Genet. 22:321-339(1998).
RN   [6]
RP   INTERACTION WITH SOSTDC1.
RX   PubMed=14623234; DOI=10.1016/j.ydbio.2003.08.011;
RA   Laurikkala J., Kassai Y., Pakkasjaervi L., Thesleff I., Itoh N.;
RT   "Identification of a secreted BMP antagonist, ectodin, integrating BMP,
RT   FGF, and SHH signals from the tooth enamel knot.";
RL   Dev. Biol. 264:91-105(2003).
RN   [7]
RP   FUNCTION, DISRUPTION PHENOTYPE, AND INTERACTION WITH HEMOJUVELIN/HJV.
RX   PubMed=19252486; DOI=10.1038/ng.335;
RA   Andriopoulos B. Jr., Corradini E., Xia Y., Faasse S.A., Chen S.,
RA   Grgurevic L., Knutson M.D., Pietrangelo A., Vukicevic S., Lin H.Y.,
RA   Babitt J.L.;
RT   "BMP6 is a key endogenous regulator of hepcidin expression and iron
RT   metabolism.";
RL   Nat. Genet. 41:482-487(2009).
RN   [8]
RP   INTERACTION WITH ERFE AND BMP6.
RX   PubMed=30097509; DOI=10.1182/blood-2018-06-857995;
RA   Arezes J., Foy N., McHugh K., Sawant A., Quinkert D., Terraube V.,
RA   Brinth A., Tam M., LaVallie E.R., Taylor S., Armitage A.E., Pasricha S.R.,
RA   Cunningham O., Lambert M., Draper S.J., Jasuja R., Drakesmith H.;
RT   "Erythroferrone inhibits the induction of hepcidin by BMP6.";
RL   Blood 132:1473-1477(2018).
RN   [9]
RP   FUNCTION, AND INTERACTION WITH ERFE; ACVR1; BMPR1A AND HUMAN BMP2.
RX   PubMed=31800957; DOI=10.1182/blood.2019002620;
RA   Wang C.Y., Xu Y., Traeger L., Dogan D.Y., Xiao X., Steinbicker A.U.,
RA   Babitt J.L.;
RT   "Erythroferrone lowers hepcidin by sequestering BMP2/6 heterodimer from
RT   binding to the BMP type I receptor ALK3.";
RL   Blood 135:453-456(2020).
RN   [10]
RP   DISRUPTION PHENOTYPE.
RX   PubMed=32464486; DOI=10.1016/j.bcmd.2020.102444;
RA   Alvarenga A.M., da Silva N.K., Fonseca P.F.S., Oliveira T.G.M.,
RA   da Silva Monteiro J.B., Cancado R.D., Naoum F.A., Dinardo C.L., Brissot P.,
RA   Santos P.C.J.L.;
RT   "Novel mutations in the bone morphogenetic protein 6 gene in patients with
RT   iron overload and non-homozygous genotype for the HFE p.Cys282Tyr
RT   mutation.";
RL   Blood Cells Mol. Dis. 84:102444-102444(2020).
CC   -!- FUNCTION: Growth factor of the TGF-beta superfamily that plays
CC       essential roles in many developmental processes including cartilage and
CC       bone formation (By similarity). Also plays an important role in the
CC       regulation of HAMP/hepcidin expression and iron metabolism by acting as
CC       a ligand for hemojuvelin/HJV (PubMed:19252486). Also acts to promote
CC       expression of HAMP, potentially via the interaction with its receptor
CC       BMPR1A/ALK3 (PubMed:31800957). Initiates the canonical BMP signaling
CC       cascade by associating with type I receptor ACVR1 and type II receptor
CC       ACVR2B. In turn, ACVR1 propagates signal by phosphorylating SMAD1/5/8
CC       that travel to the nucleus and act as activators and repressors of
CC       transcription of target. Can also signal through non-canonical pathway
CC       such as TAZ-Hippo signaling cascade to modulate VEGF signaling by
CC       regulating VEGFR2 expression (By similarity).
CC       {ECO:0000250|UniProtKB:P22004, ECO:0000269|PubMed:19252486,
CC       ECO:0000269|PubMed:31800957}.
CC   -!- SUBUNIT: Interacts with SOSTDC1 (PubMed:14623234). Interacts (when
CC       glycosylated) with type I receptor ACVR1; the interaction may induce
CC       HAMP expression (PubMed:31800957). Interacts with type II receptor
CC       ACVR2B (By similarity). Interacts with Hemojuvelin/HJV
CC       (PubMed:19252486). Interacts with ERFE; the interaction inhibits BMP-
CC       induced transcription of HAMP (PubMed:30097509, PubMed:31800957).
CC       Interacts with BMPR1A/ALK3 (PubMed:31800957). Forms heterodimers with
CC       BMP2 in vitro; the heterodimer then binds to its receptor BMPR1A /ALK3
CC       and may induce HAMP expression (PubMed:31800957).
CC       {ECO:0000250|UniProtKB:P22004, ECO:0000269|PubMed:14623234,
CC       ECO:0000269|PubMed:19252486, ECO:0000269|PubMed:30097509,
CC       ECO:0000269|PubMed:31800957}.
CC   -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250|UniProtKB:P22004}.
CC   -!- TISSUE SPECIFICITY: Expressed in the lung. Low levels seen in the
CC       kidney.
CC   -!- DISRUPTION PHENOTYPE: Deficient mice are viable and fertile without
CC       displaying overt effects in tissues known to express BMP6, suggesting a
CC       functional redundancy among the factors of this subgroup
CC       (PubMed:9664685). However, these mice show a significant increased
CC       liver iron content (PubMed:19252486, PubMed:32464486).
CC       {ECO:0000269|PubMed:19252486, ECO:0000269|PubMed:32464486,
CC       ECO:0000269|PubMed:9664685}.
CC   -!- SIMILARITY: Belongs to the TGF-beta family. {ECO:0000305}.
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DR   EMBL; X80992; CAA56917.1; -; mRNA.
DR   EMBL; U73520; AAB18235.1; -; Genomic_DNA.
DR   EMBL; U73515; AAB18235.1; JOINED; Genomic_DNA.
DR   EMBL; U73516; AAB18235.1; JOINED; Genomic_DNA.
DR   EMBL; U73517; AAB18235.1; JOINED; Genomic_DNA.
DR   EMBL; U73518; AAB18235.1; JOINED; Genomic_DNA.
DR   EMBL; U73519; AAB18235.1; JOINED; Genomic_DNA.
DR   EMBL; BC138593; AAI38594.1; -; mRNA.
DR   EMBL; BC138595; AAI38596.1; -; mRNA.
DR   EMBL; J04566; AAA40548.1; -; mRNA.
DR   CCDS; CCDS26462.1; -.
DR   PIR; A54798; A54798.
DR   RefSeq; NP_031582.1; NM_007556.3.
DR   AlphaFoldDB; P20722; -.
DR   SMR; P20722; -.
DR   BioGRID; 198366; 1.
DR   STRING; 10090.ENSMUSP00000126999; -.
DR   GlyCosmos; P20722; 5 sites, No reported glycans.
DR   GlyGen; P20722; 5 sites.
DR   iPTMnet; P20722; -.
DR   PhosphoSitePlus; P20722; -.
DR   MaxQB; P20722; -.
DR   PaxDb; 10090-ENSMUSP00000126999; -.
DR   ProteomicsDB; 273558; -.
DR   Antibodypedia; 3456; 553 antibodies from 37 providers.
DR   DNASU; 12161; -.
DR   Ensembl; ENSMUST00000171970.3; ENSMUSP00000126999.2; ENSMUSG00000039004.7.
DR   GeneID; 12161; -.
DR   KEGG; mmu:12161; -.
DR   UCSC; uc007qdp.1; mouse.
DR   AGR; MGI:88182; -.
DR   CTD; 654; -.
DR   MGI; MGI:88182; Bmp6.
DR   VEuPathDB; HostDB:ENSMUSG00000039004; -.
DR   eggNOG; KOG3900; Eukaryota.
DR   GeneTree; ENSGT00940000158768; -.
DR   HOGENOM; CLU_020515_4_1_1; -.
DR   InParanoid; P20722; -.
DR   OMA; ERQQPWP; -.
DR   OrthoDB; 2912454at2759; -.
DR   PhylomeDB; P20722; -.
DR   TreeFam; TF316134; -.
DR   BioGRID-ORCS; 12161; 2 hits in 77 CRISPR screens.
DR   ChiTaRS; Bmp6; mouse.
DR   PRO; PR:P20722; -.
DR   Proteomes; UP000000589; Chromosome 13.
DR   RNAct; P20722; Protein.
DR   Bgee; ENSMUSG00000039004; Expressed in choroid plexus of fourth ventricle and 251 other cell types or tissues.
DR   ExpressionAtlas; P20722; baseline and differential.
DR   GO; GO:0005615; C:extracellular space; HDA:BHF-UCL.
DR   GO; GO:0031982; C:vesicle; ISO:MGI.
DR   GO; GO:0070700; F:BMP receptor binding; ISO:MGI.
DR   GO; GO:0005125; F:cytokine activity; IBA:GO_Central.
DR   GO; GO:0008083; F:growth factor activity; ISO:MGI.
DR   GO; GO:0046982; F:protein heterodimerization activity; ISO:MGI.
DR   GO; GO:0030509; P:BMP signaling pathway; IDA:MGI.
DR   GO; GO:0060348; P:bone development; ISO:MGI.
DR   GO; GO:0051216; P:cartilage development; IEA:UniProtKB-KW.
DR   GO; GO:0071773; P:cellular response to BMP stimulus; ISO:MGI.
DR   GO; GO:0031668; P:cellular response to extracellular stimulus; TAS:BHF-UCL.
DR   GO; GO:0071281; P:cellular response to iron ion; IMP:BHF-UCL.
DR   GO; GO:0071260; P:cellular response to mechanical stimulus; IEA:Ensembl.
DR   GO; GO:0001958; P:endochondral ossification; IMP:MGI.
DR   GO; GO:0001654; P:eye development; IGI:UniProtKB.
DR   GO; GO:0006955; P:immune response; ISO:MGI.
DR   GO; GO:0006954; P:inflammatory response; IEP:UniProtKB.
DR   GO; GO:0006879; P:intracellular iron ion homeostasis; IMP:BHF-UCL.
DR   GO; GO:0001822; P:kidney development; IGI:UniProtKB.
DR   GO; GO:0030539; P:male genitalia development; IGI:MGI.
DR   GO; GO:0060586; P:multicellular organismal-level iron ion homeostasis; IMP:BHF-UCL.
DR   GO; GO:1903392; P:negative regulation of adherens junction organization; ISO:MGI.
DR   GO; GO:2000048; P:negative regulation of cell-cell adhesion mediated by cadherin; ISO:MGI.
DR   GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IMP:BHF-UCL.
DR   GO; GO:0030182; P:neuron differentiation; IMP:MGI.
DR   GO; GO:0001503; P:ossification; ISO:MGI.
DR   GO; GO:0001649; P:osteoblast differentiation; IGI:MGI.
DR   GO; GO:0032349; P:positive regulation of aldosterone biosynthetic process; ISO:MGI.
DR   GO; GO:2000860; P:positive regulation of aldosterone secretion; ISO:MGI.
DR   GO; GO:0030501; P:positive regulation of bone mineralization; ISO:MGI.
DR   GO; GO:0032332; P:positive regulation of chondrocyte differentiation; ISO:MGI.
DR   GO; GO:0045603; P:positive regulation of endothelial cell differentiation; IDA:DFLAT.
DR   GO; GO:0001938; P:positive regulation of endothelial cell proliferation; IDA:DFLAT.
DR   GO; GO:0050679; P:positive regulation of epithelial cell proliferation; ISO:MGI.
DR   GO; GO:0010628; P:positive regulation of gene expression; ISO:MGI.
DR   GO; GO:0031666; P:positive regulation of lipopolysaccharide-mediated signaling pathway; IMP:BHF-UCL.
DR   GO; GO:0045666; P:positive regulation of neuron differentiation; IDA:MGI.
DR   GO; GO:0045669; P:positive regulation of osteoblast differentiation; ISO:MGI.
DR   GO; GO:0050731; P:positive regulation of peptidyl-tyrosine phosphorylation; ISO:MGI.
DR   GO; GO:0060391; P:positive regulation of SMAD protein signal transduction; IMP:BHF-UCL.
DR   GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IMP:BHF-UCL.
DR   GO; GO:0043117; P:positive regulation of vascular permeability; ISO:MGI.
DR   GO; GO:0014823; P:response to activity; IEA:Ensembl.
DR   GO; GO:0051384; P:response to glucocorticoid; IEA:Ensembl.
DR   GO; GO:0032026; P:response to magnesium ion; IEA:Ensembl.
DR   GO; GO:0032526; P:response to retinoic acid; IEA:Ensembl.
DR   GO; GO:0003323; P:type B pancreatic cell development; ISO:MGI.
DR   CDD; cd19396; TGF_beta_BMP6; 1.
DR   Gene3D; 2.60.120.970; -; 1.
DR   Gene3D; 2.10.90.10; Cystine-knot cytokines; 1.
DR   InterPro; IPR029034; Cystine-knot_cytokine.
DR   InterPro; IPR001839; TGF-b_C.
DR   InterPro; IPR001111; TGF-b_propeptide.
DR   InterPro; IPR015615; TGF-beta-rel.
DR   InterPro; IPR017948; TGFb_CS.
DR   PANTHER; PTHR11848:SF137; BONE MORPHOGENETIC PROTEIN 6; 1.
DR   PANTHER; PTHR11848; TGF-BETA FAMILY; 1.
DR   Pfam; PF00019; TGF_beta; 1.
DR   Pfam; PF00688; TGFb_propeptide; 1.
DR   PRINTS; PR00669; INHIBINA.
DR   SMART; SM00204; TGFB; 1.
DR   SUPFAM; SSF57501; Cystine-knot cytokines; 1.
DR   PROSITE; PS00250; TGF_BETA_1; 1.
DR   PROSITE; PS51362; TGF_BETA_2; 1.
DR   Genevisible; P20722; MM.
PE   1: Evidence at protein level;
KW   Chondrogenesis; Cleavage on pair of basic residues; Cytokine;
KW   Developmental protein; Differentiation; Disulfide bond; Glycoprotein;
KW   Growth factor; Osteogenesis; Reference proteome; Secreted; Signal.
FT   SIGNAL          1..20
FT                   /evidence="ECO:0000255"
FT   PROPEP          21..371
FT                   /evidence="ECO:0000255"
FT                   /id="PRO_0000033872"
FT   CHAIN           372..510
FT                   /note="Bone morphogenetic protein 6"
FT                   /id="PRO_0000033873"
FT   REGION          87..129
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          143..199
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          370..402
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        160..178
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        379..402
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   CARBOHYD        238
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        266
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        383
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        401
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        451
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   DISULFID        409..475
FT                   /evidence="ECO:0000250"
FT   DISULFID        438..507
FT                   /evidence="ECO:0000250"
FT   DISULFID        442..509
FT                   /evidence="ECO:0000250"
FT   DISULFID        474
FT                   /note="Interchain"
FT                   /evidence="ECO:0000250"
FT   CONFLICT        73
FT                   /note="K -> M (in Ref. 4)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        75
FT                   /note="E -> K (in Ref. 4)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        86
FT                   /note="L -> P (in Ref. 4; AAA40548)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   510 AA;  56432 MW;  910B68531289FCD2 CRC64;
     MPGLGRRAQW LCWWWGLLCS CGPPPLRPPL PVAAAAAGGQ LLGAGGSPVR AEQPPPQSSS
     SGFLYRRLKT HEKREMQKEI LSVLGLPHRP RPLHGLQQPQ PPVLPPQQQQ QQQQQQTARE
     EPPPGRLKSA PLFMLDLYNA LSNDDEEDGA SEGVGQEPGS HGGASSSQLR QPSPGAAHSL
     NRKSLLAPGP GGGASPLTSA QDSAFLNDAD MVMSFVNLVE YDKEFSPHQR HHKEFKFNLS
     QIPEGEAVTA AEFRVYKDCV VGSFKNQTFL ISIYQVLQEH QHRDSDLFLL DTRVVWASEE
     GWLEFDITAT SNLWVVTPQH NMGLQLSVVT RDGLHVNPRA AGLVGRDGPY DKQPFMVAFF
     KVSEVHVRTT RSASSRRRQQ SRNRSTQSQD VSRGSGSSDY NGSELKTACK KHELYVSFQD
     LGWQDWIIAP KGYAANYCDG ECSFPLNAHM NATNHAIVQT LVHLMNPEYV PKPCCAPTKL
     NAISVLYFDD NSNVILKKYR NMVVRACGCH
//