GDF6_MOUSE
ID GDF6_MOUSE Reviewed; 454 AA.
AC P43028; Q70UT4;
DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
DT 11-OCT-2005, sequence version 2.
DT 03-AUG-2022, entry version 152.
DE RecName: Full=Growth/differentiation factor 6;
DE Short=GDF-6;
DE AltName: Full=Bone morphogenetic protein 13;
DE Short=BMP-13;
DE AltName: Full=Growth/differentiation factor 16;
DE Flags: Precursor;
GN Name=Gdf6; Synonyms=Bmp13, Gdf-6, Gdf16;
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 STRAIN=Kunming; TISSUE=Brain;
RA Guo J.H.;
RT "Cloning of human GDF16 and functional associated analysis.";
RL Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 330-454.
RC STRAIN=BALB/cJ; TISSUE=Liver;
RX PubMed=8145850; DOI=10.1038/368639a0;
RA Storm E.E., Huynh T.V., Copeland N.G., Jenkins N.A., Kingsley D.M.,
RA Lee S.-J.;
RT "Limb alterations in brachypodism mice due to mutations in a new member of
RT the TGF beta-superfamily.";
RL Nature 368:639-643(1994).
RN [3]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=12606286; DOI=10.1016/s0012-1606(02)00022-2;
RA Settle S.H. Jr., Rountree R.B., Sinha A., Thacker A., Higgins K.,
RA Kingsley D.M.;
RT "Multiple joint and skeletal patterning defects caused by single and double
RT mutations in the mouse Gdf6 and Gdf5 genes.";
RL Dev. Biol. 254:116-130(2003).
RN [4]
RP FUNCTION, AND IDENTIFICATION OF RECEPTORS.
RX PubMed=16049014; DOI=10.1074/jbc.m504629200;
RA Mazerbourg S., Sangkuhl K., Luo C.-W., Sudo S., Klein C., Hsueh A.J.W.;
RT "Identification of receptors and signaling pathways for orphan bone
RT morphogenetic protein/growth differentiation factor ligands based on
RT genomic analyses.";
RL J. Biol. Chem. 280:32122-32132(2005).
RN [5]
RP FUNCTION.
RX PubMed=23527555; DOI=10.1111/febs.12256;
RA Wang S.S., Huang H.Y., Chen S.Z., Li X., Zhang W.T., Tang Q.Q.;
RT "Gdf6 induces commitment of pluripotent mesenchymal C3H10T1/2 cells to the
RT adipocyte lineage.";
RL FEBS J. 280:2644-2651(2013).
RN [6]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=23307924; DOI=10.1093/hmg/dds560;
RA Asai-Coakwell M., March L., Dai X.H., Duval M., Lopez I., French C.R.,
RA Famulski J., De Baere E., Francis P.J., Sundaresan P., Sauve Y.,
RA Koenekoop R.K., Berry F.B., Allison W.T., Waskiewicz A.J., Lehmann O.J.;
RT "Contribution of growth differentiation factor 6-dependent cell survival to
RT early-onset retinal dystrophies.";
RL Hum. Mol. Genet. 22:1432-1442(2013).
RN [7]
RP INDUCTION.
RX PubMed=24076600; DOI=10.1038/ng.2772;
RA Sartori R., Schirwis E., Blaauw B., Bortolanza S., Zhao J., Enzo E.,
RA Stantzou A., Mouisel E., Toniolo L., Ferry A., Stricker S., Goldberg A.L.,
RA Dupont S., Piccolo S., Amthor H., Sandri M.;
RT "BMP signaling controls muscle mass.";
RL Nat. Genet. 45:1309-1318(2013).
RN [8]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=26774823; DOI=10.1016/j.cell.2015.12.007;
RA Indjeian V.B., Kingman G.A., Jones F.C., Guenther C.A., Grimwood J.,
RA Schmutz J., Myers R.M., Kingsley D.M.;
RT "Evolving new skeletal traits by cis-regulatory changes in bone
RT morphogenetic proteins.";
RL Cell 164:45-56(2016).
RN [9]
RP TISSUE SPECIFICITY, AND DISRUPTION PHENOTYPE.
RX PubMed=32369452; DOI=10.1172/jci136951;
RA Bademci G., Abad C., Cengiz F.B., Seyhan S., Incesulu A., Guo S., Fitoz S.,
RA Atli E.I., Gosstola N.C., Demir S., Colbert B.M., Seyhan G.C., Sineni C.J.,
RA Duman D., Gurkan H., Morton C.C., Dykxhoorn D.M., Walz K., Tekin M.;
RT "Long-range cis-regulatory elements controlling GDF6 expression are
RT essential for ear development.";
RL J. Clin. Invest. 130:4213-4217(2020).
CC -!- FUNCTION: Growth factor that controls proliferation and cellular
CC differentiation in the retina and bone formation. Plays a key role in
CC regulating apoptosis during retinal development. Establishes dorsal-
CC ventral positional information in the retina and controls the formation
CC of the retinotectal map (PubMed:23307924). Required for normal
CC formation of bones and joints in the limbs, skull, digits and axial
CC skeleton. Plays a key role in establishing boundaries between skeletal
CC elements during development. Regulation of GDF6 expression seems to be
CC a mechanism for evolving species-specific changes in skeletal
CC structures (PubMed:26774823). Seems to positively regulate
CC differentiation of chondrogenic tissue through the growth factor
CC receptors subunits BMPR1A, BMPR1B, BMPR2 and ACVR2A, leading to the
CC activation of SMAD1-SMAD5-SMAD8 complex. The regulation of chondrogenic
CC differentiation is inhibited by NOG (PubMed:12606286, PubMed:16049014).
CC Also involved in the induction of adipogenesis from mesenchymal stem
CC cells. This mechanism acts through the growth factor receptors subunits
CC BMPR1A, BMPR2 and ACVR2A and the activation of SMAD1-SMAD5-SMAD8
CC complex and MAPK14/p38 (PubMed:23527555). {ECO:0000269|PubMed:12606286,
CC ECO:0000269|PubMed:16049014, ECO:0000269|PubMed:23307924,
CC ECO:0000269|PubMed:23527555, ECO:0000269|PubMed:26774823}.
CC -!- SUBUNIT: Homodimer; disulfide-linked. {ECO:0000250|UniProtKB:P39905}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250|UniProtKB:Q6KF10}.
CC -!- TISSUE SPECIFICITY: Expressed in different subsets of developing
CC joints. Highly expressed in the cochlea (PubMed:32369452).
CC {ECO:0000269|PubMed:12606286, ECO:0000269|PubMed:32369452}.
CC -!- INDUCTION: Strongly up-regulated in tibialis anterior muscles after
CC denervation. {ECO:0000269|PubMed:24076600}.
CC -!- DISRUPTION PHENOTYPE: Mice lacking GDF6 display photoreceptor
CC degeneration. Animals exhibit abnormal electroretinograms with up to
CC 66% decreases in the bipolar cell-driven b-wave and 54% decreases in
CC the photoreceptor-mediated a-wave amplitudes, as well as 3 to 27%
CC reduced photopic flicker fusion. The lengths, but not the widths, of
CC dermal flat bones in the skull and the digits are significantly shorter
CC than in wild type (PubMed:26774823). GDF6-knockout mice also shows
CC cochlear aplasia, while the vestibular anatomy is normal
CC (PubMed:32369452). {ECO:0000269|PubMed:23307924,
CC ECO:0000269|PubMed:26774823, ECO:0000269|PubMed:32369452}.
CC -!- SIMILARITY: Belongs to the TGF-beta 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; AJ537425; CAD60935.1; -; mRNA.
DR EMBL; U08338; AAA18779.1; -; Unassigned_DNA.
DR CCDS; CCDS17960.1; -.
DR PIR; S43295; S43295.
DR RefSeq; NP_038554.1; NM_013526.1.
DR AlphaFoldDB; P43028; -.
DR SMR; P43028; -.
DR STRING; 10090.ENSMUSP00000062884; -.
DR GlyGen; P43028; 1 site.
DR iPTMnet; P43028; -.
DR PhosphoSitePlus; P43028; -.
DR PaxDb; P43028; -.
DR PRIDE; P43028; -.
DR ProteomicsDB; 267787; -.
DR Antibodypedia; 25942; 166 antibodies from 29 providers.
DR DNASU; 242316; -.
DR Ensembl; ENSMUST00000057613; ENSMUSP00000062884; ENSMUSG00000051279.
DR GeneID; 242316; -.
DR KEGG; mmu:242316; -.
DR UCSC; uc008ryt.1; mouse.
DR CTD; 392255; -.
DR MGI; MGI:95689; Gdf6.
DR VEuPathDB; HostDB:ENSMUSG00000051279; -.
DR eggNOG; KOG3900; Eukaryota.
DR GeneTree; ENSGT00940000162274; -.
DR HOGENOM; CLU_020515_0_0_1; -.
DR InParanoid; P43028; -.
DR OMA; KKSKYRC; -.
DR OrthoDB; 749511at2759; -.
DR PhylomeDB; P43028; -.
DR TreeFam; TF316134; -.
DR BioGRID-ORCS; 242316; 1 hit in 71 CRISPR screens.
DR PRO; PR:P43028; -.
DR Proteomes; UP000000589; Chromosome 4.
DR RNAct; P43028; protein.
DR Bgee; ENSMUSG00000051279; Expressed in auditory ossicle bone and 51 other tissues.
DR ExpressionAtlas; P43028; baseline and differential.
DR GO; GO:0005615; C:extracellular space; HDA:BHF-UCL.
DR GO; GO:0005125; F:cytokine activity; IBA:GO_Central.
DR GO; GO:0008083; F:growth factor activity; IEA:UniProtKB-KW.
DR GO; GO:0042802; F:identical protein binding; IPI:MGI.
DR GO; GO:0048018; F:receptor ligand activity; TAS:MGI.
DR GO; GO:0032924; P:activin receptor signaling pathway; ISO:MGI.
DR GO; GO:0006915; P:apoptotic process; ISS:UniProtKB.
DR GO; GO:0030509; P:BMP signaling pathway; IDA:MGI.
DR GO; GO:0035788; P:cell migration involved in metanephros development; IMP:MGI.
DR GO; GO:0045444; P:fat cell differentiation; IMP:UniProtKB.
DR GO; GO:0072170; P:metanephric tubule development; ISO:MGI.
DR GO; GO:0001656; P:metanephros development; IMP:MGI.
DR GO; GO:0060389; P:pathway-restricted SMAD protein phosphorylation; ISO:MGI.
DR GO; GO:0032332; P:positive regulation of chondrocyte differentiation; ISS:UniProtKB.
DR GO; GO:0045666; P:positive regulation of neuron differentiation; IDA:MGI.
DR GO; GO:1900745; P:positive regulation of p38MAPK cascade; IMP:UniProtKB.
DR GO; GO:0010862; P:positive regulation of pathway-restricted SMAD protein phosphorylation; ISO:MGI.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; ISO:MGI.
DR GO; GO:1990009; P:retinal cell apoptotic process; ISS:UniProtKB.
DR GO; GO:0060395; P:SMAD protein signal transduction; IMP:UniProtKB.
DR Gene3D; 2.10.90.10; -; 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; PTHR11848; 1.
DR Pfam; PF00019; TGF_beta; 1.
DR Pfam; PF00688; TGFb_propeptide; 1.
DR SMART; SM00204; TGFB; 1.
DR SUPFAM; SSF57501; SSF57501; 1.
DR PROSITE; PS00250; TGF_BETA_1; 1.
DR PROSITE; PS51362; TGF_BETA_2; 1.
PE 2: Evidence at transcript level;
KW Apoptosis; Cleavage on pair of basic residues; Cytokine;
KW Developmental protein; Disulfide bond; Glycoprotein; Growth factor;
KW Reference proteome; Secreted; Signal.
FT SIGNAL 1..22
FT /evidence="ECO:0000255"
FT PROPEP 23..334
FT /evidence="ECO:0000255"
FT /id="PRO_0000342207"
FT CHAIN 335..454
FT /note="Growth/differentiation factor 6"
FT /id="PRO_0000033919"
FT REGION 28..93
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 247..268
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 303..350
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 41..56
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 64..81
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 333..350
FT /note="Basic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT CARBOHYD 117
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 353..419
FT /evidence="ECO:0000250|UniProtKB:P39905"
FT DISULFID 382..451
FT /evidence="ECO:0000250|UniProtKB:P39905"
FT DISULFID 386..453
FT /evidence="ECO:0000250|UniProtKB:P39905"
FT DISULFID 418
FT /note="Interchain"
FT /evidence="ECO:0000250|UniProtKB:P39905"
SQ SEQUENCE 454 AA; 50942 MW; 5A3FADDA539CCB38 CRC64;
MDTPRVLLWA IFLISFLWDL PGFQQASISS SSSSSTELDS TKDVGNRKEG KMQRTPQESA
EGRTPPEHGL RQKDLRRRPP GQHQGQEPPG RGLRVVPHEY MLSIYKTYSI AEKLGINASF
FQSSKSANTI TSFVDRGLDD LSHTPLRRQK YLFDVSTLSD KEELVGAELR LYRQAPPTPW
GLPARPLHLQ LFPCLSPLLL DARTLDPQGP TQAGWEVFDV WQGLRPQPWK QLCLELRAAW
GELDAGDTGA RARGPQQPPP LDLRSLGFGR RVRPPQERAL LVVFTRSQRK NLFTEMHEQL
GSAEAAGAEG SWPAPSGSPD AGSWLPSPGR RRRRTAFASR HGKRHGKKSR LRCSRKPLHV
NFKELGWDDW IIAPLEYEAY HCEGVCDFPL RSHLEPTNHA IIQTLMNSMD PGSTPPSCCV
PTKLTPISIL YIDAGNNVVY KQYEDMVVES CGCR
