GDF3_HUMAN
ID GDF3_HUMAN Reviewed; 364 AA.
AC Q9NR23; Q8NEJ4;
DT 21-FEB-2001, integrated into UniProtKB/Swiss-Prot.
DT 13-APR-2004, sequence version 3.
DT 03-AUG-2022, entry version 167.
DE RecName: Full=Growth/differentiation factor 3;
DE Short=GDF-3;
DE Flags: Precursor;
GN Name=GDF3; ORFNames=UNQ222/PRO248;
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].
RA Lorenz B., White K.E., Econs M.J., Strom T.M.;
RT "Transcripts in human map region 12p13.3.";
RL Submitted (MAY-2000) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=12975309; DOI=10.1101/gr.1293003;
RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J.,
RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P.,
RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S., Huang A.,
RA Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D.,
RA Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L.,
RA Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C.,
RA Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J.,
RA Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.;
RT "The secreted protein discovery initiative (SPDI), a large-scale effort to
RT identify novel human secreted and transmembrane proteins: a bioinformatics
RT assessment.";
RL Genome Res. 13:2265-2270(2003).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16541075; DOI=10.1038/nature04569;
RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y.,
RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C.,
RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M., Kovar-Smith C.,
RA Lewis L.R., Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R.,
RA Montgomery K.T., Morgan M.B., Nazareth L.V., Scott G., Sodergren E.,
RA Song X.-Z., Steffen D., Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y.,
RA Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G.,
RA Chen Z., Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H.,
RA Draper H., Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S.,
RA Kelly S.H., Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M.,
RA Nguyen B.-V., Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H.,
RA Santibanez J., Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q.,
RA Williams G.A., Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V.,
RA Bailey M., Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E.,
RA Burkett C.E., Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K.,
RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D.,
RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M., Dathorne S.R.,
RA David R., Davis C.M., Davy-Carroll L., Deshazo D.R., Donlin J.E.,
RA D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J., Escotto M., Flagg N.,
RA Forbes L.D., Gabisi A.M., Garza M., Hamilton C., Henderson N.,
RA Hernandez O., Hines S., Hogues M.E., Huang M., Idlebird D.G., Johnson R.,
RA Jolivet A., Jones S., Kagan R., King L.M., Leal B., Lebow H., Lee S.,
RA LeVan J.M., Lewis L.C., London P., Lorensuhewa L.M., Loulseged H.,
RA Lovett D.A., Lucier A., Lucier R.L., Ma J., Madu R.C., Mapua P.,
RA Martindale A.D., Martinez E., Massey E., Mawhiney S., Meador M.G.,
RA Mendez S., Mercado C., Mercado I.C., Merritt C.E., Miner Z.L., Minja E.,
RA Mitchell T., Mohabbat F., Mohabbat K., Montgomery B., Moore N., Morris S.,
RA Munidasa M., Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O.,
RA Nwokenkwo S., Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J.,
RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A.,
RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M.,
RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I.,
RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A.,
RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D., Trejos Z.Y.,
RA Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I., Vera V.A.,
RA Villasana D.M., Wang L., Ward-Moore S., Warren J.T., Wei X., White F.,
RA Williamson A.L., Wleczyk R., Wooden H.S., Wooden S.H., Yen J., Yoon L.,
RA Yoon V., Zorrilla S.E., Nelson D., Kucherlapati R., Weinstock G.,
RA Gibbs R.A.;
RT "The finished DNA sequence of human chromosome 12.";
RL Nature 440:346-351(2006).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT ARG-213.
RC TISSUE=Kidney;
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 [5]
RP SUBCELLULAR LOCATION, AND FUNCTION AS LIGAND FOR ACVR1C.
RX PubMed=21805089; DOI=10.1007/s11010-011-1005-0;
RA Li Q., Liu X., Wu Y., An J., Hexige S., Ling Y., Zhang M., Yang X., Yu L.;
RT "The conditioned medium from a stable human GDF3-expressing CHO cell line,
RT induces the differentiation of PC12 cells.";
RL Mol. Cell. Biochem. 359:115-123(2012).
RN [6]
RP VARIANT KFS3 CYS-266, VARIANTS MCOP7 GLN-195 AND PRO-305, VARIANTS MCOPCB6
RP CYS-266 AND TRP-274, CHARACTERIZATION OF VARIANTS MCOP7 GLN-195 AND
RP PRO-305, CHARACTERIZATION OF VARIANT KFS3 CYS-266, AND SUBCELLULAR
RP LOCATION.
RX PubMed=19864492; DOI=10.1093/hmg/ddp496;
RA Ye M., Berry-Wynne K.M., Asai-Coakwell M., Sundaresan P., Footz T.,
RA French C.R., Abitbol M., Fleisch V.C., Corbett N., Allison W.T.,
RA Drummond G., Walter M.A., Underhill T.M., Waskiewicz A.J., Lehmann O.J.;
RT "Mutation of the bone morphogenetic protein GDF3 causes ocular and skeletal
RT anomalies.";
RL Hum. Mol. Genet. 19:287-298(2010).
CC -!- FUNCTION: Growth factor involved in early embryonic development and
CC adipose-tissue homeostasis. During embryogenesis controls formation of
CC anterior visceral endoderm and mesoderm and the establishment of
CC anterior-posterior identity through a receptor complex comprising the
CC receptor ACVR1B and the coreceptor TDGF1/Cripto (By similarity).
CC Regulates adipose-tissue homeostasis and energy balance under nutrient
CC overload in part by signaling through the receptor complex based on
CC ACVR1C and TDGF1/Cripto (PubMed:21805089).
CC {ECO:0000250|UniProtKB:Q07104, ECO:0000269|PubMed:21805089}.
CC -!- SUBUNIT: Homodimer or heterodimer (Potential). But, in contrast to
CC other members of this family, cannot be disulfide-linked.
CC {ECO:0000305}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:19864492,
CC ECO:0000269|PubMed:21805089}. Cytoplasm {ECO:0000269|PubMed:19864492,
CC ECO:0000269|PubMed:21805089}. Note=Mainly accumulated in the cytoplasm.
CC {ECO:0000269|PubMed:21805089}.
CC -!- PTM: Synthesized as large precursor molecule that undergo proteolytic
CC cleavage, releasing the pro-domain from the active, receptor binding,
CC C-terminal region of the molecule. {ECO:0000305}.
CC -!- DISEASE: Klippel-Feil syndrome 3, autosomal dominant (KFS3)
CC [MIM:613702]: A skeletal disorder characterized by congenital fusion of
CC cervical vertebrae. It is due to a failure in the normal segmentation
CC of vertebrae during the early weeks of fetal development. The clinical
CC triad consists of short neck, low posterior hairline, and limited neck
CC movement. {ECO:0000269|PubMed:19864492}. Note=The disease is caused by
CC variants affecting the gene represented in this entry.
CC -!- DISEASE: Microphthalmia, isolated, with coloboma, 6 (MCOPCB6)
CC [MIM:613703]: A disorder of eye formation, ranging from small size of a
CC single eye to complete bilateral absence of ocular tissues. Ocular
CC abnormalities like opacities of the cornea and lens, scaring of the
CC retina and choroid, and other abnormalities may also be present. Ocular
CC colobomas are a set of malformations resulting from abnormal
CC morphogenesis of the optic cup and stalk, and the fusion of the fetal
CC fissure (optic fissure). {ECO:0000269|PubMed:19864492}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Microphthalmia, isolated, 7 (MCOP7) [MIM:613704]: A disorder
CC of eye formation, ranging from small size of a single eye to complete
CC bilateral absence of ocular tissues. Ocular abnormalities like
CC opacities of the cornea and lens, scaring of the retina and choroid,
CC and other abnormalities may also be present.
CC {ECO:0000269|PubMed:19864492}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: In contrast to other members of this family, cannot be
CC disulfide-linked due to an atypical cysteine knot configuration, where
CC the fourth cysteine is missing. This fourth cysteine is involved in an
CC inter-molecular bridge to stabilize the active form of homodimeric or
CC heterodimeric signaling molecules. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the TGF-beta family. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Wikipedia; Note=GDF3 entry;
CC URL="https://en.wikipedia.org/wiki/GDF3";
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DR EMBL; AF263538; AAF91389.1; -; mRNA.
DR EMBL; AY358875; AAQ89234.1; -; mRNA.
DR EMBL; AC006927; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC030959; AAH30959.1; -; mRNA.
DR CCDS; CCDS8581.1; -.
DR RefSeq; NP_065685.1; NM_020634.2.
DR AlphaFoldDB; Q9NR23; -.
DR SMR; Q9NR23; -.
DR BioGRID; 114942; 13.
DR IntAct; Q9NR23; 3.
DR STRING; 9606.ENSP00000331745; -.
DR GlyGen; Q9NR23; 2 sites.
DR PhosphoSitePlus; Q9NR23; -.
DR BioMuta; GDF3; -.
DR DMDM; 46397885; -.
DR EPD; Q9NR23; -.
DR MassIVE; Q9NR23; -.
DR PaxDb; Q9NR23; -.
DR PeptideAtlas; Q9NR23; -.
DR PRIDE; Q9NR23; -.
DR ProteomicsDB; 82261; -.
DR Antibodypedia; 11440; 424 antibodies from 32 providers.
DR DNASU; 9573; -.
DR Ensembl; ENST00000329913.4; ENSP00000331745.3; ENSG00000184344.4.
DR GeneID; 9573; -.
DR KEGG; hsa:9573; -.
DR MANE-Select; ENST00000329913.4; ENSP00000331745.3; NM_020634.3; NP_065685.1.
DR UCSC; uc001qte.4; human.
DR CTD; 9573; -.
DR DisGeNET; 9573; -.
DR GeneCards; GDF3; -.
DR HGNC; HGNC:4218; GDF3.
DR HPA; ENSG00000184344; Tissue enhanced (kidney).
DR MalaCards; GDF3; -.
DR MIM; 606522; gene.
DR MIM; 613702; phenotype.
DR MIM; 613703; phenotype.
DR MIM; 613704; phenotype.
DR neXtProt; NX_Q9NR23; -.
DR OpenTargets; ENSG00000184344; -.
DR Orphanet; 98938; Colobomatous microphthalmia.
DR Orphanet; 2345; Isolated Klippel-Feil syndrome.
DR PharmGKB; PA28633; -.
DR VEuPathDB; HostDB:ENSG00000184344; -.
DR eggNOG; KOG3900; Eukaryota.
DR GeneTree; ENSGT00940000162534; -.
DR HOGENOM; CLU_020515_4_0_1; -.
DR InParanoid; Q9NR23; -.
DR OMA; NYCHGDC; -.
DR OrthoDB; 919690at2759; -.
DR PhylomeDB; Q9NR23; -.
DR TreeFam; TF351789; -.
DR PathwayCommons; Q9NR23; -.
DR SignaLink; Q9NR23; -.
DR BioGRID-ORCS; 9573; 5 hits in 1068 CRISPR screens.
DR GeneWiki; GDF3; -.
DR GenomeRNAi; 9573; -.
DR Pharos; Q9NR23; Tbio.
DR PRO; PR:Q9NR23; -.
DR Proteomes; UP000005640; Chromosome 12.
DR RNAct; Q9NR23; protein.
DR Bgee; ENSG00000184344; Expressed in metanephros cortex and 79 other tissues.
DR Genevisible; Q9NR23; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
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:0019901; F:protein kinase binding; IPI:UniProtKB.
DR GO; GO:0030509; P:BMP signaling pathway; IBA:GO_Central.
DR GO; GO:0007492; P:endoderm development; IEA:Ensembl.
DR GO; GO:0001654; P:eye development; IMP:UniProtKB.
DR GO; GO:0048859; P:formation of anatomical boundary; IEA:Ensembl.
DR GO; GO:0001701; P:in utero embryonic development; IEA:Ensembl.
DR GO; GO:0007498; P:mesoderm development; IEA:Ensembl.
DR GO; GO:0030514; P:negative regulation of BMP signaling pathway; IDA:UniProtKB.
DR GO; GO:0045605; P:negative regulation of epidermal cell differentiation; IDA:UniProtKB.
DR GO; GO:0045662; P:negative regulation of myoblast differentiation; IEA:Ensembl.
DR GO; GO:0030903; P:notochord development; IEA:Ensembl.
DR GO; GO:0045600; P:positive regulation of fat cell differentiation; ISS:BHF-UCL.
DR GO; GO:0010862; P:positive regulation of pathway-restricted SMAD protein phosphorylation; IBA:GO_Central.
DR GO; GO:0090009; P:primitive streak formation; IEA:Ensembl.
DR GO; GO:0010453; P:regulation of cell fate commitment; IDA:UniProtKB.
DR GO; GO:0002021; P:response to dietary excess; IEA:Ensembl.
DR GO; GO:0001501; P:skeletal system development; IMP:UniProtKB.
DR GO; GO:0060395; P:SMAD protein signal transduction; IBA:GO_Central.
DR GO; GO:0032525; P:somite rostral/caudal axis specification; IEA:Ensembl.
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 Cleavage on pair of basic residues; Cytokine; Cytoplasm;
KW Developmental protein; Disease variant; Disulfide bond; Glycoprotein;
KW Growth factor; Microphthalmia; Reference proteome; Secreted; Signal.
FT SIGNAL 1..24
FT /evidence="ECO:0000255"
FT PROPEP 25..250
FT /evidence="ECO:0000255"
FT /id="PRO_0000033908"
FT CHAIN 251..364
FT /note="Growth/differentiation factor 3"
FT /id="PRO_0000033909"
FT CARBOHYD 112
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 306
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 264..329
FT /evidence="ECO:0000250"
FT DISULFID 293..361
FT /evidence="ECO:0000250"
FT DISULFID 297..363
FT /evidence="ECO:0000250"
FT VARIANT 195
FT /note="R -> Q (in MCOP7; reduces the amount of active
FT ligand secreted; dbSNP:rs146973734)"
FT /evidence="ECO:0000269|PubMed:19864492"
FT /id="VAR_065147"
FT VARIANT 213
FT /note="G -> R (in dbSNP:rs12819884)"
FT /evidence="ECO:0000269|PubMed:15489334"
FT /id="VAR_052574"
FT VARIANT 266
FT /note="R -> C (in KFS3 and MCOPCB6; reduces the amount of
FT active ligand secreted; reduced amout of mature protein in
FT the cytosol; dbSNP:rs140926412)"
FT /evidence="ECO:0000269|PubMed:19864492"
FT /id="VAR_065148"
FT VARIANT 274
FT /note="R -> W (in MCOPCB6; dbSNP:rs387906946)"
FT /evidence="ECO:0000269|PubMed:19864492"
FT /id="VAR_065149"
FT VARIANT 305
FT /note="L -> P (in MCOP7; also detected in a patient with
FT bilateral iris coloboma; reduces the amount of active
FT ligand secreted; dbSNP:rs387906945)"
FT /evidence="ECO:0000269|PubMed:19864492"
FT /id="VAR_065150"
FT VARIANT 328
FT /note="V -> L (in dbSNP:rs2302516)"
FT /id="VAR_020064"
SQ SEQUENCE 364 AA; 41387 MW; E0D2EA86E2B73A0B CRC64;
MLRFLPDLAF SFLLILALGQ AVQFQEYVFL QFLGLDKAPS PQKFQPVPYI LKKIFQDREA
AATTGVSRDL CYVKELGVRG NVLRFLPDQG FFLYPKKISQ ASSCLQKLLY FNLSAIKERE
QLTLAQLGLD LGPNSYYNLG PELELALFLV QEPHVWGQTT PKPGKMFVLR SVPWPQGAVH
FNLLDVAKDW NDNPRKNFGL FLEILVKEDR DSGVNFQPED TCARLRCSLH ASLLVVTLNP
DQCHPSRKRR AAIPVPKLSC KNLCHRHQLF INFRDLGWHK WIIAPKGFMA NYCHGECPFS
LTISLNSSNY AFMQALMHAV DPEIPQAVCI PTKLSPISML YQDNNDNVIL RHYEDMVVDE
CGCG
