GDF2_MOUSE
ID GDF2_MOUSE Reviewed; 428 AA.
AC Q9WV56; Q3ZAS6; Q9QZE0;
DT 21-FEB-2001, integrated into UniProtKB/Swiss-Prot.
DT 27-JUL-2011, sequence version 2.
DT 03-AUG-2022, entry version 148.
DE RecName: Full=Growth/differentiation factor 2;
DE Short=GDF-2;
DE AltName: Full=Bone morphogenetic protein 9;
DE Short=BMP-9;
DE Flags: Precursor;
GN Name=Gdf2; Synonyms=Bmp9;
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=CD-1; TISSUE=Liver;
RA Zimmers T.A., Koniaris L.G., Sitzmann J.V., Lee S.-J.;
RT "Growth/differentiation factor-2, a new TGF-beta family member with bone
RT promoting activities.";
RL Submitted (JUN-1999) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Liver;
RA Celeste A.J.;
RL Submitted (SEP-1999) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Liver;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 [6]
RP FUNCTION.
RX PubMed=23300529; DOI=10.1371/journal.pone.0050920;
RA Nolan-Stevaux O., Zhong W., Culp S., Shaffer K., Hoover J.,
RA Wickramasinghe D., Ruefli-Brasse A.;
RT "Endoglin requirement for BMP9 signaling in endothelial cells reveals new
RT mechanism of action for selective anti-endoglin antibodies.";
RL PLoS ONE 7:E50920-E50920(2012).
RN [7] {ECO:0007744|PDB:4YCG, ECO:0007744|PDB:4YCI}
RP X-RAY CRYSTALLOGRAPHY (3.25 ANGSTROMS) OF 23-318, FUNCTION, GLYCOSYLATION
RP AT ASN-135, DISULFIDE BONDS, SUBUNIT, AND INTERACTION WITH ACVRL1; BMPR2;
RP ACVR2B AND ACVR2A.
RX PubMed=25751889; DOI=10.1073/pnas.1501303112;
RA Mi L.Z., Brown C.T., Gao Y., Tian Y., Le V.Q., Walz T., Springer T.A.;
RT "Structure of bone morphogenetic protein 9 procomplex.";
RL Proc. Natl. Acad. Sci. U.S.A. 112:3710-3715(2015).
CC -!- FUNCTION: Potent circulating inhibitor of angiogenesis (By similarity).
CC Signals through the type I activin receptor ACVRL1 but not other Alks
CC (PubMed:25751889). Signaling through SMAD1 in endothelial cells
CC requires TGF-beta coreceptor endoglin/ENG (PubMed:23300529).
CC {ECO:0000250|UniProtKB:Q9UK05, ECO:0000269|PubMed:23300529,
CC ECO:0000269|PubMed:25751889}.
CC -!- SUBUNIT: Homodimer; disulfide-linked. Detected in extracellular fluid
CC as mature homodimer, and in complex with its propeptide (By
CC similarity). Interacts with ACVRL1, BMPR2 and ACVR2B with high affinity
CC (in vitro) (PubMed:25751889). Identified in a complex with ACVRL1 and
CC ACVR2B (By similarity). Has ten times lower affinity for ACVR2A (in
CC vitro) (PubMed:25751889). Interacts with ENG, forming a heterotetramer
CC with a 2:2 stoichiometry. Can form a heteromeric complex with ENG and
CC ACVRL1 (By similarity). Interacts with type I receptor ACVR1 (By
CC similarity). {ECO:0000250|UniProtKB:Q9UK05,
CC ECO:0000269|PubMed:25751889}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250|UniProtKB:Q9UK05}.
CC -!- PTM: A reversible disulfide bond can be formed between the two subunits
CC in the homodimer; this has no effect on GDF2 activity.
CC {ECO:0000250|UniProtKB:Q9UK05}.
CC -!- SIMILARITY: Belongs to the TGF-beta family. {ECO:0000305}.
CC -!- CAUTION: Can promote osteogenic differentiation in vitro
CC (PubMed:25751889). This is probably not physiologically relevant.
CC {ECO:0000269|PubMed:25751889, ECO:0000305}.
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DR EMBL; AF156890; AAD40308.1; -; mRNA.
DR EMBL; AF188286; AAD56961.1; -; mRNA.
DR EMBL; AK147029; BAE27621.1; -; mRNA.
DR EMBL; CH466573; EDL24862.1; -; Genomic_DNA.
DR EMBL; BC103625; AAI03626.1; -; mRNA.
DR EMBL; BC103679; AAI03680.1; -; mRNA.
DR EMBL; BC103680; AAI03681.1; -; mRNA.
DR EMBL; BC103681; AAI03682.1; -; mRNA.
DR CCDS; CCDS26928.1; -.
DR RefSeq; NP_062379.3; NM_019506.4.
DR PDB; 4YCG; X-ray; 3.30 A; A/B=23-318.
DR PDB; 4YCI; X-ray; 3.25 A; A/B=23-318.
DR PDBsum; 4YCG; -.
DR PDBsum; 4YCI; -.
DR AlphaFoldDB; Q9WV56; -.
DR SMR; Q9WV56; -.
DR BioGRID; 198370; 1.
DR STRING; 10090.ENSMUSP00000098286; -.
DR GlyGen; Q9WV56; 3 sites.
DR iPTMnet; Q9WV56; -.
DR PhosphoSitePlus; Q9WV56; -.
DR MaxQB; Q9WV56; -.
DR PaxDb; Q9WV56; -.
DR PRIDE; Q9WV56; -.
DR ProteomicsDB; 267785; -.
DR Antibodypedia; 72423; 376 antibodies from 35 providers.
DR DNASU; 12165; -.
DR Ensembl; ENSMUST00000100720; ENSMUSP00000098286; ENSMUSG00000072625.
DR GeneID; 12165; -.
DR KEGG; mmu:12165; -.
DR UCSC; uc007tac.1; mouse.
DR CTD; 2658; -.
DR MGI; MGI:1321394; Gdf2.
DR VEuPathDB; HostDB:ENSMUSG00000072625; -.
DR eggNOG; KOG3900; Eukaryota.
DR GeneTree; ENSGT00940000159802; -.
DR HOGENOM; CLU_020515_2_0_1; -.
DR InParanoid; Q9WV56; -.
DR OMA; GTFDLRM; -.
DR OrthoDB; 749511at2759; -.
DR PhylomeDB; Q9WV56; -.
DR TreeFam; TF316134; -.
DR Reactome; R-MMU-201451; Signaling by BMP.
DR BioGRID-ORCS; 12165; 2 hits in 72 CRISPR screens.
DR PRO; PR:Q9WV56; -.
DR Proteomes; UP000000589; Chromosome 14.
DR RNAct; Q9WV56; protein.
DR Bgee; ENSMUSG00000072625; Expressed in hepatobiliary system and 29 other tissues.
DR Genevisible; Q9WV56; MM.
DR GO; GO:0005615; C:extracellular space; IBA:GO_Central.
DR GO; GO:0005125; F:cytokine activity; IBA:GO_Central.
DR GO; GO:0008083; F:growth factor activity; IEA:UniProtKB-KW.
DR GO; GO:0032924; P:activin receptor signaling pathway; ISO:MGI.
DR GO; GO:0001525; P:angiogenesis; ISS:UniProtKB.
DR GO; GO:0048514; P:blood vessel morphogenesis; ISO:MGI.
DR GO; GO:0030509; P:BMP signaling pathway; ISO:MGI.
DR GO; GO:0001569; P:branching involved in blood vessel morphogenesis; IDA:DFLAT.
DR GO; GO:0006879; P:cellular iron ion homeostasis; TAS:DFLAT.
DR GO; GO:0071773; P:cellular response to BMP stimulus; ISO:MGI.
DR GO; GO:0006006; P:glucose metabolic process; TAS:DFLAT.
DR GO; GO:0030308; P:negative regulation of cell growth; ISO:MGI.
DR GO; GO:2000279; P:negative regulation of DNA biosynthetic process; ISO:MGI.
DR GO; GO:0010596; P:negative regulation of endothelial cell migration; ISO:MGI.
DR GO; GO:0001937; P:negative regulation of endothelial cell proliferation; ISO:MGI.
DR GO; GO:0030182; P:neuron differentiation; TAS:DFLAT.
DR GO; GO:0001649; P:osteoblast differentiation; IGI:MGI.
DR GO; GO:0060389; P:pathway-restricted SMAD protein phosphorylation; ISO:MGI.
DR GO; GO:0045766; P:positive regulation of angiogenesis; IDA:DFLAT.
DR GO; GO:0030513; P:positive regulation of BMP signaling pathway; IDA:DFLAT.
DR GO; GO:0061036; P:positive regulation of cartilage development; IDA:UniProtKB.
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:0010628; P:positive regulation of gene expression; IDA:MGI.
DR GO; GO:0032757; P:positive regulation of interleukin-8 production; ISO:MGI.
DR GO; GO:0010862; P:positive regulation of pathway-restricted SMAD protein phosphorylation; ISO:MGI.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:MGI.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IMP:DFLAT.
DR GO; GO:0060395; P:SMAD protein signal transduction; IBA:GO_Central.
DR GO; GO:0006366; P:transcription by RNA polymerase II; IDA:MGI.
DR GO; GO:0001570; P:vasculogenesis; IDA:DFLAT.
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 1: Evidence at protein level;
KW 3D-structure; Angiogenesis; Cleavage on pair of basic residues; Cytokine;
KW Disulfide bond; Glycoprotein; Growth factor; Reference proteome; Secreted;
KW Signal.
FT SIGNAL 1..22
FT /evidence="ECO:0000255"
FT PROPEP 23..318
FT /evidence="ECO:0000250"
FT /id="PRO_0000033904"
FT CHAIN 319..428
FT /note="Growth/differentiation factor 2"
FT /id="PRO_0000033905"
FT REGION 401..415
FT /note="Interaction with ENG"
FT /evidence="ECO:0000250|UniProtKB:Q9UK05"
FT CARBOHYD 70
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 135
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:25751889,
FT ECO:0007744|PDB:4YCG, ECO:0007744|PDB:4YCI"
FT CARBOHYD 262
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 155..236
FT /evidence="ECO:0000269|PubMed:25751889,
FT ECO:0007744|PDB:4YCG, ECO:0007744|PDB:4YCI"
FT DISULFID 326..392
FT /evidence="ECO:0000250|UniProtKB:Q9UK05"
FT DISULFID 355..425
FT /evidence="ECO:0000250|UniProtKB:Q9UK05"
FT DISULFID 359..427
FT /evidence="ECO:0000250|UniProtKB:Q9UK05"
FT DISULFID 391
FT /note="Interchain"
FT /evidence="ECO:0000250|UniProtKB:Q9UK05"
FT CONFLICT 293
FT /note="V -> G (in Ref. 1; AAD40308)"
FT /evidence="ECO:0000305"
FT CONFLICT 382
FT /note="K -> E (in Ref. 2; AAD56961)"
FT /evidence="ECO:0000305"
FT HELIX 86..96
FT /evidence="ECO:0007829|PDB:4YCI"
FT STRAND 106..112
FT /evidence="ECO:0007829|PDB:4YCI"
FT STRAND 115..119
FT /evidence="ECO:0007829|PDB:4YCI"
FT STRAND 123..125
FT /evidence="ECO:0007829|PDB:4YCI"
FT STRAND 127..133
FT /evidence="ECO:0007829|PDB:4YCI"
FT STRAND 142..155
FT /evidence="ECO:0007829|PDB:4YCI"
FT HELIX 161..163
FT /evidence="ECO:0007829|PDB:4YCI"
FT STRAND 167..176
FT /evidence="ECO:0007829|PDB:4YCI"
FT STRAND 185..196
FT /evidence="ECO:0007829|PDB:4YCI"
FT STRAND 198..205
FT /evidence="ECO:0007829|PDB:4YCI"
FT HELIX 207..214
FT /evidence="ECO:0007829|PDB:4YCI"
FT TURN 217..219
FT /evidence="ECO:0007829|PDB:4YCI"
FT STRAND 223..231
FT /evidence="ECO:0007829|PDB:4YCI"
FT STRAND 233..235
FT /evidence="ECO:0007829|PDB:4YCI"
FT STRAND 239..241
FT /evidence="ECO:0007829|PDB:4YCI"
FT STRAND 252..259
FT /evidence="ECO:0007829|PDB:4YCI"
FT TURN 260..263
FT /evidence="ECO:0007829|PDB:4YCI"
FT HELIX 264..277
FT /evidence="ECO:0007829|PDB:4YCI"
SQ SEQUENCE 428 AA; 47703 MW; 82E4475FF8B27F36 CRC64;
MSPGAFRVAL LPLFLLVCVT QQKPLQNWEQ ASPGENAHSS LGLSGAGEEG VFDLQMFLEN
MKVDFLRSLN LSGIPSQDKT RAEPPQYMID LYNRYTTDKS STPASNIVRS FSVEDAISTA
ATEDFPFQKH ILIFNISIPR HEQITRAELR LYVSCQNDVD STHGLEGSMV VYDVLEDSET
WDQATGTKTF LVSQDIRDEG WETLEVSSAV KRWVRADSTT NKNKLEVTVQ SHRESCDTLD
ISVPPGSKNL PFFVVFSNDR SNGTKETRLE LKEMIGHEQE TMLVKTAKNA YQVAGESQEE
EGLDGYTAVG PLLARRKRST GASSHCQKTS LRVNFEDIGW DSWIIAPKEY DAYECKGGCF
FPLADDVTPT KHAIVQTLVH LKFPTKVGKA CCVPTKLSPI SILYKDDMGV PTLKYHYEGM
SVAECGCR
