GDF15_MOUSE
ID GDF15_MOUSE Reviewed; 303 AA.
AC Q9Z0J7; Q6NX63;
DT 21-FEB-2001, integrated into UniProtKB/Swiss-Prot.
DT 03-OCT-2012, sequence version 2.
DT 03-AUG-2022, entry version 138.
DE RecName: Full=Growth/differentiation factor 15 {ECO:0000305};
DE Short=GDF-15 {ECO:0000305};
DE AltName: Full=Macrophage inhibitory cytokine 1 {ECO:0000305};
DE Short=MIC-1 {ECO:0000303|PubMed:23468844, ECO:0000303|PubMed:28081177};
DE Flags: Precursor;
GN Name=Gdf15 {ECO:0000312|MGI:MGI:1346047};
GN Synonyms=Mic1 {ECO:0000303|PubMed:23468844, ECO:0000303|PubMed:28081177},
GN Sbf;
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 [GENOMIC DNA].
RC STRAIN=129/SvJ;
RA Boettner M., Laaff M., Suter-Crazzolara C.;
RT "Identification of a novel member of the TGFbeta superfamily.";
RL Submitted (OCT-1998) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY.
RX PubMed=10779363; DOI=10.1128/mcb.20.10.3742-3751.2000;
RA Hsiao E.C., Koniaris L.G., Zimmers-Koniaris T., Sebald S.M., Huynh T.V.,
RA Lee S.-J.;
RT "Characterization of growth-differentiation factor 15, a transforming
RT growth factor beta superfamily member induced following liver injury.";
RL Mol. Cell. Biol. 20:3742-3751(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J;
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].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [5]
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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Mammary gland;
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 [7]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=23468844; DOI=10.1371/journal.pone.0055174;
RA Tsai V.W., Macia L., Johnen H., Kuffner T., Manadhar R., Joergensen S.B.,
RA Lee-Ng K.K., Zhang H.P., Wu L., Marquis C.P., Jiang L., Husaini Y., Lin S.,
RA Herzog H., Brown D.A., Sainsbury A., Breit S.N.;
RT "TGF-b superfamily cytokine MIC-1/GDF15 is a physiological appetite and
RT body weight regulator.";
RL PLoS ONE 8:E55174-E55174(2013).
RN [8]
RP FUNCTION, TISSUE SPECIFICITY, DEVELOPMENTAL STAGE, AND SUBCELLULAR
RP LOCATION.
RX PubMed=28572090; DOI=10.15252/emmm.201707604;
RA Wang T., Liu J., McDonald C., Lupino K., Zhai X., Wilkins B.J.,
RA Hakonarson H., Pei L.;
RT "GDF15 is a heart-derived hormone that regulates body growth.";
RL EMBO Mol. Med. 9:1150-1164(2017).
RN [9]
RP FUNCTION.
RX PubMed=28953886; DOI=10.1038/nature24042;
RA Hsu J.Y., Crawley S., Chen M., Ayupova D.A., Lindhout D.A., Higbee J.,
RA Kutach A., Joo W., Gao Z., Fu D., To C., Mondal K., Li B., Kekatpure A.,
RA Wang M., Laird T., Horner G., Chan J., McEntee M., Lopez M.,
RA Lakshminarasimhan D., White A., Wang S.P., Yao J., Yie J., Matern H.,
RA Solloway M., Haldankar R., Parsons T., Tang J., Shen W.D., Alice Chen Y.,
RA Tian H., Allan B.B.;
RT "Non-homeostatic body weight regulation through a brainstem-restricted
RT receptor for GDF15.";
RL Nature 550:255-259(2017).
RN [10]
RP ERRATUM OF PUBMED:28953886.
RX PubMed=29144449; DOI=10.1038/nature24481;
RA Hsu J.Y., Crawley S., Chen M., Ayupova D.A., Lindhout D.A., Higbee J.,
RA Kutach A., Joo W., Gao Z., Fu D., To C., Mondal K., Li B., Kekatpure A.,
RA Wang M., Laird T., Horner G., Chan J., McEntee M., Lopez M.,
RA Lakshminarasimhan D., White A., Wang S.P., Yao J., Yie J., Matern H.,
RA Solloway M., Haldankar R., Parsons T., Tang J., Shen W.D., Alice Chen Y.,
RA Tian H., Allan B.B.;
RT "Non-homeostatic body weight regulation through a brainstem-restricted
RT receptor for GDF15.";
RL Nature 551:398-398(2017).
RN [11]
RP FUNCTION.
RX PubMed=28846097; DOI=10.1038/nm.4392;
RA Mullican S.E., Lin-Schmidt X., Chin C.N., Chavez J.A., Furman J.L.,
RA Armstrong A.A., Beck S.C., South V.J., Dinh T.Q., Cash-Mason T.D.,
RA Cavanaugh C.R., Nelson S., Huang C., Hunter M.J., Rangwala S.M.;
RT "GFRAL is the receptor for GDF15 and the ligand promotes weight loss in
RT mice and nonhuman primates.";
RL Nat. Med. 23:1150-1157(2017).
RN [12]
RP FUNCTION, AND INTERACTION WITH GFRAL.
RX PubMed=28846099; DOI=10.1038/nm.4394;
RA Yang L., Chang C.C., Sun Z., Madsen D., Zhu H., Padkjaer S.B., Wu X.,
RA Huang T., Hultman K., Paulsen S.J., Wang J., Bugge A., Frantzen J.B.,
RA Noergaard P., Jeppesen J.F., Yang Z., Secher A., Chen H., Li X., John L.M.,
RA Shan B., He Z., Gao X., Su J., Hansen K.T., Yang W., Joergensen S.B.;
RT "GFRAL is the receptor for GDF15 and is required for the anti-obesity
RT effects of the ligand.";
RL Nat. Med. 23:1158-1166(2017).
RN [13]
RP INTERACTION WITH GFRAL.
RX PubMed=28846098; DOI=10.1038/nm.4393;
RA Emmerson P.J., Wang F., Du Y., Liu Q., Pickard R.T., Gonciarz M.D.,
RA Coskun T., Hamang M.J., Sindelar D.K., Ballman K.K., Foltz L.A.,
RA Muppidi A., Alsina-Fernandez J., Barnard G.C., Tang J.X., Liu X., Mao X.,
RA Siegel R., Sloan J.H., Mitchell P.J., Zhang B.B., Gimeno R.E., Shan B.,
RA Wu X.;
RT "The metabolic effects of GDF15 are mediated by the orphan receptor
RT GFRAL.";
RL Nat. Med. 23:1215-1219(2017).
RN [14]
RP DISRUPTION PHENOTYPE.
RX PubMed=28081177; DOI=10.1371/journal.pone.0168416;
RA Low J.K., Ambikairajah A., Shang K., Brown D.A., Tsai V.W., Breit S.N.,
RA Karl T.;
RT "First behavioral Characterisation of a Knockout Mouse Model for the
RT Transforming Growth Factor (TGF)-beta Superfamily Cytokine, MIC-1/GDF15.";
RL PLoS ONE 12:E0168416-E0168416(2017).
RN [15]
RP INDUCTION BY OBESITY, TISSUE SPECIFICITY, SUBCELLULAR LOCATION, AND
RP FUNCTION.
RX PubMed=29046435; DOI=10.1126/scitranslmed.aan8732;
RA Xiong Y., Walker K., Min X., Hale C., Tran T., Komorowski R., Yang J.,
RA Davda J., Nuanmanee N., Kemp D., Wang X., Liu H., Miller S., Lee K.J.,
RA Wang Z., Veniant M.M.;
RT "Long-acting MIC-1/GDF15 molecules to treat obesity: Evidence from mice to
RT monkeys.";
RL Sci. Transl. Med. 9:0-0(2017).
CC -!- FUNCTION: Regulates food intake, energy expenditure and body weight in
CC response to metabolic and toxin-induced stresses. Binds to its
CC receptor, GFRAL, and activates GFRAL-expressing neurons localized in
CC the area postrema and nucleus tractus solitarius of the brainstem. It
CC then triggers the activation of neurons localized within the
CC parabrachial nucleus and central amygdala, which constitutes part of
CC the 'emergency circuit' that shapes feeding responses to stressful
CC conditions (PubMed:28953886, PubMed:28846097, PubMed:28846099,
CC PubMed:28572090, PubMed:23468844, PubMed:29046435). On hepatocytes,
CC inhibits growth hormone signaling (PubMed:28572090).
CC {ECO:0000269|PubMed:23468844, ECO:0000269|PubMed:28572090,
CC ECO:0000269|PubMed:28846097, ECO:0000269|PubMed:28846099,
CC ECO:0000269|PubMed:28953886, ECO:0000269|PubMed:29046435}.
CC -!- SUBUNIT: Homodimer; disulfide-linked (By similarity). Interacts with
CC GFRAL; ligand of GFRAL which mediates GDF15 internalization and
CC cellular signaling through interaction with RET (PubMed:28846098,
CC PubMed:28846099). {ECO:0000250|UniProtKB:Q99988,
CC ECO:0000269|PubMed:28846098, ECO:0000269|PubMed:28846099}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:28572090,
CC ECO:0000269|PubMed:29046435}.
CC -!- TISSUE SPECIFICITY: Highly expressed in liver (PubMed:10779363,
CC PubMed:28572090, PubMed:29046435). Detected in plasma (at protein
CC level) (PubMed:28572090, PubMed:29046435). Expressed by cardiomyocytes,
CC expression is highly increased in heart diseases (PubMed:28572090).
CC Also detected in subcutaneous fat (PubMed:28572090, PubMed:29046435).
CC {ECO:0000269|PubMed:10779363, ECO:0000269|PubMed:28572090,
CC ECO:0000269|PubMed:29046435}.
CC -!- DEVELOPMENTAL STAGE: At postnatal day 3 (P3), detected in heart and
CC plasma, expression decreases with lower levels at P7 to, at least, P13.
CC {ECO:0000269|PubMed:28572090}.
CC -!- INDUCTION: Expression is up-regulated by obesity.
CC {ECO:0000269|PubMed:29046435}.
CC -!- DISRUPTION PHENOTYPE: Mutants weight more, have increases adiposity
CC associated with increased spontaneous food intake and exhibit reduced
CC basal energy expenditure and physical activity (PubMed:23468844).
CC Female mutants exhibit some additional alterations in reduced basal
CC energy expenditure and physical activity (PubMed:23468844). At
CC behavioral level, they exhibit a task-dependent increase in locomotion
CC and exploration and reduced anxiety-related behaviors across tests.
CC Their spatial working memory and social behaviors are not affected.
CC They form an increased association with conditioned stimulus in fear
CC conditioning testing and also display significantly improved prepulse
CC inhibition (PubMed:28081177). {ECO:0000269|PubMed:23468844,
CC ECO:0000269|PubMed:28081177}.
CC -!- SIMILARITY: Belongs to the TGF-beta family. {ECO:0000305}.
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DR EMBL; AJ011967; CAA09890.1; -; Genomic_DNA.
DR EMBL; AJ011968; CAA09890.1; JOINED; Genomic_DNA.
DR EMBL; AF159571; AAD41410.1; -; mRNA.
DR EMBL; AK159242; BAE34924.1; -; mRNA.
DR EMBL; AC157774; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH466569; EDL28851.1; -; Genomic_DNA.
DR EMBL; BC067248; AAH67248.1; -; mRNA.
DR CCDS; CCDS22376.1; -.
DR RefSeq; NP_001317616.1; NM_001330687.1.
DR RefSeq; NP_035949.2; NM_011819.3.
DR AlphaFoldDB; Q9Z0J7; -.
DR SMR; Q9Z0J7; -.
DR STRING; 10090.ENSMUSP00000003808; -.
DR GlyGen; Q9Z0J7; 1 site.
DR PhosphoSitePlus; Q9Z0J7; -.
DR MaxQB; Q9Z0J7; -.
DR PaxDb; Q9Z0J7; -.
DR PRIDE; Q9Z0J7; -.
DR ProteomicsDB; 271205; -.
DR Antibodypedia; 2781; 907 antibodies from 40 providers.
DR DNASU; 23886; -.
DR Ensembl; ENSMUST00000003808; ENSMUSP00000003808; ENSMUSG00000038508.
DR Ensembl; ENSMUST00000110103; ENSMUSP00000105730; ENSMUSG00000038508.
DR GeneID; 23886; -.
DR KEGG; mmu:23886; -.
DR UCSC; uc009mba.2; mouse.
DR CTD; 9518; -.
DR MGI; MGI:1346047; Gdf15.
DR VEuPathDB; HostDB:ENSMUSG00000038508; -.
DR eggNOG; KOG3900; Eukaryota.
DR GeneTree; ENSGT00940000161872; -.
DR HOGENOM; CLU_064099_1_0_1; -.
DR InParanoid; Q9Z0J7; -.
DR OMA; RCCRLHT; -.
DR OrthoDB; 776672at2759; -.
DR PhylomeDB; Q9Z0J7; -.
DR TreeFam; TF351787; -.
DR BioGRID-ORCS; 23886; 2 hits in 73 CRISPR screens.
DR ChiTaRS; Gdf15; mouse.
DR PRO; PR:Q9Z0J7; -.
DR Proteomes; UP000000589; Chromosome 8.
DR RNAct; Q9Z0J7; protein.
DR Bgee; ENSMUSG00000038508; Expressed in stroma of bone marrow and 36 other tissues.
DR Genevisible; Q9Z0J7; MM.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005576; C:extracellular region; IDA:UniProtKB.
DR GO; GO:0005615; C:extracellular space; ISS:UniProtKB.
DR GO; GO:0005794; C:Golgi apparatus; ISO:MGI.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0070700; F:BMP receptor binding; 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:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0030509; P:BMP signaling pathway; IBA:GO_Central.
DR GO; GO:0035860; P:glial cell-derived neurotrophic factor receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0060400; P:negative regulation of growth hormone receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0040015; P:negative regulation of multicellular organism growth; IDA:UniProtKB.
DR GO; GO:0043410; P:positive regulation of MAPK cascade; IMP:GO_Central.
DR GO; GO:1901741; P:positive regulation of myoblast fusion; IMP:MGI.
DR GO; GO:0010862; P:positive regulation of pathway-restricted SMAD protein phosphorylation; IBA:GO_Central.
DR GO; GO:0051897; P:positive regulation of protein kinase B signaling; ISS:UniProtKB.
DR GO; GO:0002023; P:reduction of food intake in response to dietary excess; IDA:UniProtKB.
DR GO; GO:0060395; P:SMAD protein signal transduction; ISS:UniProtKB.
DR Gene3D; 2.10.90.10; -; 1.
DR InterPro; IPR029034; Cystine-knot_cytokine.
DR InterPro; IPR001839; TGF-b_C.
DR InterPro; IPR015615; TGF-beta-rel.
DR PANTHER; PTHR11848; PTHR11848; 1.
DR Pfam; PF00019; TGF_beta; 1.
DR SMART; SM00204; TGFB; 1.
DR SUPFAM; SSF57501; SSF57501; 1.
DR PROSITE; PS51362; TGF_BETA_2; 1.
PE 1: Evidence at protein level;
KW Cleavage on pair of basic residues; Cytokine; Disulfide bond; Glycoprotein;
KW Growth factor; Reference proteome; Secreted; Signal.
FT SIGNAL 1..30
FT /evidence="ECO:0000255"
FT PROPEP 31..188
FT /evidence="ECO:0000255"
FT /id="PRO_0000033994"
FT CHAIN 189..303
FT /note="Growth/differentiation factor 15"
FT /id="PRO_0000033995"
FT CARBOHYD 71
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 198..205
FT /evidence="ECO:0000250|UniProtKB:Q99988"
FT DISULFID 206..269
FT /evidence="ECO:0000250|UniProtKB:Q99988"
FT DISULFID 235..300
FT /evidence="ECO:0000250|UniProtKB:Q99988"
FT DISULFID 239..302
FT /evidence="ECO:0000250|UniProtKB:Q99988"
FT DISULFID 268
FT /note="Interchain"
FT /evidence="ECO:0000250"
FT CONFLICT 45
FT /note="P -> R (in Ref. 1; CAA09890 and 2; AAD41410)"
FT /evidence="ECO:0000305"
FT CONFLICT 132
FT /note="A -> T (in Ref. 1; CAA09890 and 2; AAD41410)"
FT /evidence="ECO:0000305"
FT CONFLICT 148
FT /note="R -> Q (in Ref. 1; CAA09890 and 2; AAD41410)"
FT /evidence="ECO:0000305"
FT CONFLICT 173
FT /note="T -> A (in Ref. 1; CAA09890 and 2; AAD41410)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 303 AA; 33225 MW; CD021EBEF598D3D0 CRC64;
MAPPALQAQP PGGSQLRFLL FLLLLLLLLS WPSQGDALAM PEQRPSGPES QLNADELRGR
FQDLLSRLHA NQSREDSNSE PSPDPAVRIL SPEVRLGSHG QLLLRVNRAS LSQGLPEAYR
VHRALLLLTP TARPWDITRP LKRALSLRGP RAPALRLRLT PPPDLAMLPS GGTQLELRLR
VAAGRGRRSA HAHPRDSCPL GPGRCCHLET VQATLEDLGW SDWVLSPRQL QLSMCVGECP
HLYRSANTHA QIKARLHGLQ PDKVPAPCCV PSSYTPVVLM HRTDSGVSLQ TYDDLVARGC
HCA
