ID GDF15_RAT Reviewed; 303 AA.
AC Q9Z0J6;
DT 21-FEB-2001, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-1999, sequence version 1.
DT 27-MAR-2024, entry version 116.
DE RecName: Full=Growth/differentiation factor 15;
DE Short=GDF-15;
DE Flags: Precursor;
GN Name=Gdf15; Synonyms=Sbf;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
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 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 [3]
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 [4]
RP FUNCTION.
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 [5]
RP INDUCTION BY OBESITY, TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION.
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 (Probable). On hepatocytes, inhibits growth hormone
CC signaling (By similarity). {ECO:0000250|UniProtKB:Q9Z0J7,
CC ECO:0000305|PubMed:28846099, ECO:0000305|PubMed:28953886}.
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 (By similarity).
CC {ECO:0000250|UniProtKB:Q99988, ECO:0000250|UniProtKB:Q9Z0J7}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:29046435}.
CC -!- TISSUE SPECIFICITY: Detected in plasma (at protein level).
CC {ECO:0000269|PubMed:29046435}.
CC -!- INDUCTION: Expression is up-regulated by obesity.
CC {ECO:0000269|PubMed:29046435}.
CC -!- SIMILARITY: Belongs to the TGF-beta family. {ECO:0000305}.
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DR EMBL; AJ011969; CAA09891.1; -; Genomic_DNA.
DR EMBL; AJ011970; CAA09891.1; JOINED; Genomic_DNA.
DR RefSeq; NP_062089.1; NM_019216.2.
DR AlphaFoldDB; Q9Z0J6; -.
DR SMR; Q9Z0J6; -.
DR STRING; 10116.ENSRNOP00000026652; -.
DR GlyCosmos; Q9Z0J6; 1 site, No reported glycans.
DR GlyGen; Q9Z0J6; 1 site.
DR PhosphoSitePlus; Q9Z0J6; -.
DR PaxDb; 10116-ENSRNOP00000026652; -.
DR GeneID; 29455; -.
DR KEGG; rno:29455; -.
DR UCSC; RGD:2674; rat.
DR AGR; RGD:2674; -.
DR CTD; 9518; -.
DR RGD; 2674; Gdf15.
DR eggNOG; KOG3900; Eukaryota.
DR InParanoid; Q9Z0J6; -.
DR OrthoDB; 3015718at2759; -.
DR PhylomeDB; Q9Z0J6; -.
DR PRO; PR:Q9Z0J6; -.
DR Proteomes; UP000002494; Unplaced.
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:0005634; C:nucleus; ISS:UniProtKB.
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: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; ISS:UniProtKB.
DR GO; GO:0040015; P:negative regulation of multicellular organism growth; ISS:UniProtKB.
DR GO; GO:0043410; P:positive regulation of MAPK cascade; ISS:UniProtKB.
DR GO; GO:1901741; P:positive regulation of myoblast fusion; ISO:RGD.
DR GO; GO:0051897; P:positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; ISS:UniProtKB.
DR GO; GO:0002023; P:reduction of food intake in response to dietary excess; ISS:UniProtKB.
DR GO; GO:0060395; P:SMAD protein signal transduction; ISS:UniProtKB.
DR Gene3D; 2.10.90.10; Cystine-knot cytokines; 1.
DR InterPro; IPR029034; Cystine-knot_cytokine.
DR InterPro; IPR001839; TGF-b_C.
DR InterPro; IPR015615; TGF-beta-rel.
DR PANTHER; PTHR11848:SF78; GROWTH_DIFFERENTIATION FACTOR 15; 1.
DR PANTHER; PTHR11848; TGF-BETA FAMILY; 1.
DR Pfam; PF00019; TGF_beta; 1.
DR SMART; SM00204; TGFB; 1.
DR SUPFAM; SSF57501; Cystine-knot cytokines; 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_0000033996"
FT CHAIN 189..303
FT /note="Growth/differentiation factor 15"
FT /id="PRO_0000033997"
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"
SQ SEQUENCE 303 AA; 33439 MW; FA828BE79C1052C9 CRC64;
MALRALHAQP TGGPQLRFLL FLLLLLLLLS WPSQGDALAL PEQRRSLSES QLNPDELRGR
FQDLLSRLHA NQSREDSNSE PTPDPAVRIL SPEVRLGSHG RLLLRVNRAS LTQGLPEAYR
VHRALLLLTP SSRPWDITRP LQRAISLQGP HARALRLRLA PPPDLAVLPS GGARLELHLR
SAAGRGRRSA HLHPRDSCPL GPGRCCHLET VQATLEDLGW SDWVLSPRQL QLSMCVGECP
HLYRSANTHA LIKARLHGLQ PDRVPAPCCV PSSYTPVVLM HRTDSGVSLQ TYDDLVAQGC
HCA
//