{"entryType":"UniProtKB reviewed (Swiss-Prot)","primaryAccession":"Q99988","secondaryAccessions":["O14629","P78360","Q9BWA0","Q9NRT0"],"uniProtkbId":"GDF15_HUMAN","entryAudit":{"firstPublicDate":"2001-02-21","lastAnnotationUpdateDate":"2026-09-02","lastSequenceUpdateDate":"2010-11-30","entryVersion":202,"sequenceVersion":3},"annotationScore":5.0,"organism":{"scientificName":"Homo sapiens","commonName":"Human","taxonId":9606,"lineage":["Eukaryota","Metazoa","Chordata","Craniata","Vertebrata","Euteleostomi","Mammalia","Eutheria","Euarchontoglires","Primates","Haplorrhini","Catarrhini","Hominidae","Homo"]},"proteinExistence":"1: Evidence at protein level","proteinDescription":{"recommendedName":{"fullName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"23468844"}],"value":"Growth/differentiation factor 15"},"shortNames":[{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"23468844"}],"value":"GDF-15"}]},"alternativeNames":[{"fullName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"28846099"}],"value":"Macrophage inhibitory cytokine 1"},"shortNames":[{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"28846099"}],"value":"MIC-1"}]},{"fullName":{"value":"NSAID-activated gene 1 protein"},"shortNames":[{"value":"NAG-1"}]},{"fullName":{"value":"NSAID-regulated gene 1 protein"},"shortNames":[{"value":"NRG-1"}]},{"fullName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"9375789"}],"value":"Placental TGF-beta"}},{"fullName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"9375789"}],"value":"Placental bone morphogenetic protein"}},{"fullName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"9593718"}],"value":"Prostate differentiation factor"}}],"flag":"Precursor"},"genes":[{"geneName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"23468844"},{"evidenceCode":"ECO:0000312","source":"HGNC","id":"HGNC:30142"}],"value":"GDF15"},"synonyms":[{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"28846099"}],"value":"MIC1"},{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"9593718"}],"value":"PDF"},{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"9375789"}],"value":"PLAB"},{"value":"PTGFB"}]}],"comments":[{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q9Z0J7"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"23468844"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24971956"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28846097"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28846098"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28846099"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28953886"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"29046435"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30639358"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"31402172"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"31535977"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"31875646"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32661391"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33589633"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"36001956"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"37060902"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"38092039"}],"value":"Hormone produced in response to various stresses to confer information about those stresses to the brain, and trigger an aversive response, characterized by nausea, vomiting, and/or loss of appetite (PubMed:23468844, PubMed:24971956, PubMed:28846097, PubMed:28846098, PubMed:28846099, PubMed:28953886, PubMed:29046435, PubMed:30639358, PubMed:31875646, PubMed:33589633, PubMed:38092039). The aversive response is both required to reduce continuing exposure to those stresses at the time of exposure and to promote avoidance behavior in the future (PubMed:30639358, PubMed:33589633, PubMed:38092039). Acts by binding to its receptor, GFRAL, activating GFRAL-expressing neurons localized in the area postrema and nucleus tractus solitarius of the brainstem (PubMed:28846097, PubMed:28846098, PubMed:28846099, PubMed:28953886, PubMed:31535977). It then triggers the activation of neurons localized within the parabrachial nucleus and central amygdala, which constitutes part of the 'emergency circuit' that shapes responses to stressful conditions (PubMed:28953886). The GDF15-GFRAL signal induces expression of genes involved in metabolism, such as lipid metabolism in adipose tissues (PubMed:31402172). Required for avoidance behavior in response to food allergens: induced downstream of mast cell activation to promote aversion and minimize harmful effects of exposure to noxious substances (By similarity). In addition to suppress appetite, also promotes weight loss by enhancing energy expenditure in muscle: acts by increasing calcium futile cycling in muscle (By similarity). Contributes to the effect of metformin, an anti-diabetic drug, on appetite reduction and weight loss: produced in the kidney in response to metformin treatment, thereby activating the GDF15-GFRAL response, leading to reduced appetite and weight (PubMed:31875646, PubMed:37060902). The contribution of GDF15 to weight loss following metformin treatment is however limited and subject to discussion (PubMed:36001956). Produced in response to anticancer drugs, such as camptothecin or cisplatin, promoting nausea, vomiting and contributing to malnutrition (By similarity). Overproduced in many cancers, promoting anorexia in cancer (cachexia) (PubMed:32661391). Responsible for the risk of nausea and vomiting during pregnancy: high levels of GDF15 during pregnancy, mostly originating from the fetus, are associated with increased nausea and vomiting (PubMed:38092039). Maternal sensitivity to nausea is probably determined by pre-pregnancy exposure to GDF15, women with naturally high level of GDF15 being less susceptible to nausea than women with low levels of GDF15 before pregnancy (PubMed:38092039). Promotes metabolic adaptation in response to systemic inflammation caused by bacterial and viral infections in order to promote tissue tolerance and prevent tissue damage (PubMed:31402172). Required for tissue tolerance in response to myocardial infarction by acting as an inhibitor of leukocyte integring activation, thereby protecting against cardiac rupture (By similarity). Inhibits growth hormone signaling on hepatocytes (By similarity)"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28846097"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28846098"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28846099"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28953886"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"29046435"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"31535977"}],"value":"Homodimer; disulfide-linked (PubMed:29046435, PubMed:31535977). Interacts with GFRAL and RET; ligand of GFRAL, which mediates GDF15 internalization and cellular signaling through interaction with RET via the formation of a 2:2:2 ternary complex composed of GDF15, GFRAL and RET (PubMed:28846097, PubMed:28846098, PubMed:28846099, PubMed:28953886, PubMed:31535977)"}],"commentType":"SUBUNIT"},{"commentType":"INTERACTION","interactions":[{"interactantOne":{"uniProtKBAccession":"Q99988","intActId":"EBI-2116863"},"interactantTwo":{"uniProtKBAccession":"Q13185","geneName":"CBX3","intActId":"EBI-78176"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q99988","intActId":"EBI-2116863"},"interactantTwo":{"uniProtKBAccession":"Q6UXV0","geneName":"GFRAL","intActId":"EBI-27112718"},"numberOfExperiments":2,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q99988","intActId":"EBI-2116863"},"interactantTwo":{"uniProtKBAccession":"P49639","geneName":"HOXA1","intActId":"EBI-740785"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q99988","intActId":"EBI-2116863"},"interactantTwo":{"uniProtKBAccession":"P59991","geneName":"KRTAP12-2","intActId":"EBI-10176379"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q99988","intActId":"EBI-2116863"},"interactantTwo":{"uniProtKBAccession":"Q99750","geneName":"MDFI","intActId":"EBI-724076"},"numberOfExperiments":5,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q99988","intActId":"EBI-2116863"},"interactantTwo":{"uniProtKBAccession":"Q9Y6A5","geneName":"TACC3","intActId":"EBI-2554984"},"numberOfExperiments":3,"organismDiffer":false}]},{"commentType":"SUBCELLULAR LOCATION","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28572090"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"29046435"}],"value":"Secreted in the plasma"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28572090"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"29046435"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"31875646"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32694673"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"38092039"}],"value":"Secreted","id":"SL-0243"}}]},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28572090"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"29046435"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"37060902"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"9348093"}],"value":"Detected in plasma (at protein level) (PubMed:28572090, PubMed:29046435). Highly expressed in placenta, with lower levels in prostate and colon and some expression in kidney (PubMed:37060902, PubMed:9348093)"}],"commentType":"TISSUE SPECIFICITY"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"29046435"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30639358"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"31402172"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"31875646"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32694673"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33207247"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33589633"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"36001956"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"38056430"}],"value":"Produced in response to various stresses, such as metabolic and toxin-induced stresses or drugs (PubMed:31402172, PubMed:31875646, PubMed:32694673, PubMed:33207247, PubMed:33589633, PubMed:36001956). Expression is activated by ATF4 and DDIT3/CHOP transcription factors downstream of the integrated stress response (ISR) (PubMed:30639358). Expressed in response to inflammatory conditions (PubMed:31402172). Expression is induced by metformin, a blood-glucose-lowering drug (PubMed:31875646, PubMed:32694673, PubMed:36001956). Expression is induced by cisplatin anticancer drug (PubMed:33207247). Also induced by physical activity (PubMed:33589633). Expression is up-regulated by obesity (PubMed:29046435). Expression is up-regulated by ketogenic diet (PubMed:38056430)"}],"commentType":"INDUCTION"},{"commentType":"DISEASE","disease":{"diseaseId":"Hyperemesis gravidarum","diseaseAccession":"DI-06832","acronym":"HG","description":"An autosomal dominant condition characterized by severe nausea and vomiting in pregnancy. It occurs in up to 2% of pregnancies and leads to significant weight loss, dehydration, electrolyte imbalance, and ketonuria. It is associated with both maternal and fetal morbidity.","diseaseCrossReference":{"database":"MIM","id":"620730"},"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"29563502"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"35218128"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"38092039"}]},"note":{"texts":[{"value":"Disease susceptibility is associated with variants affecting the gene represented in this entry"}]}},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"31875646"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"36630958"}],"value":"GDF15 was initially considered as a promising factor for the treatment of obesity due to its ability of GDF15 to reduce appetite and promote weight loss (PubMed:31875646). However, while activation of the GDF15-GFRAL signaling pathway is efficient to reduce obesity and promote weight loss in mouse, it only has limited effect in human (PubMed:36630958)"}],"commentType":"MISCELLANEOUS"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"Belongs to the TGF-beta family"}],"commentType":"SIMILARITY"},{"commentType":"WEB RESOURCE","resourceName":"Atlas of Genetics and Cytogenetics in Oncology and Haematology","resourceUrl":"https://atlasgeneticsoncology.org/gene/40701/GDF15","ftp":false},{"commentType":"WEB RESOURCE","resourceName":"Protein Spotlight","resourceUrl":"https://www.proteinspotlight.org/back_issues/270/","ftp":false,"note":"Nausea - Issue 270 of July 2024"}],"features":[{"type":"Signal","location":{"start":{"value":1,"modifier":"EXACT"},"end":{"value":29,"modifier":"EXACT"}},"description":"","evidences":[{"evidenceCode":"ECO:0000255"}]},{"type":"Propeptide","location":{"start":{"value":30,"modifier":"EXACT"},"end":{"value":194,"modifier":"EXACT"}},"description":"","evidences":[{"evidenceCode":"ECO:0000255"}],"featureId":"PRO_0000033992"},{"type":"Chain","location":{"start":{"value":195,"modifier":"EXACT"},"end":{"value":308,"modifier":"EXACT"}},"description":"Growth/differentiation factor 15","featureId":"PRO_0000033993"},{"type":"Region","location":{"start":{"value":152,"modifier":"EXACT"},"end":{"value":177,"modifier":"EXACT"}},"description":"Disordered","evidences":[{"evidenceCode":"ECO:0000256","source":"SAM","id":"MobiDB-lite"}]},{"type":"Compositional bias","location":{"start":{"value":165,"modifier":"EXACT"},"end":{"value":177,"modifier":"EXACT"}},"description":"Polar 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