Growth/differentiation Factor 15 (GDF-15, also called as MIC-1, NAG-1 and NRG-1, Uniprot: Q99988) is a divergent member of the TGF-b superfamily of growth factors. It is encoded in humans by a gene in chromosome 19. The human GDF-15 gene encodes for a protein of 308 amino acid residues which consists of a signal sequence (residues 1-29), pro-domain (30-194) and mature growth factor domain (195-308). The protein is secreted from the producing cell and the precursor containing the pro- and mature domains is proteolytically processed by furin-like protease, typically in the Golgi complex, but sometimes also an unprocessed protein is secreted. Two mature domains dimerize forming a typical TGF-b-like structure with four b-strands and an a-helix in each protomer, with an interfacial disulfide stabilizing the mature growth factor. The molecular weight of a mature GDF-15 dimer is 25 kDa.

Mature GDF-15 has its dedicated GFRAL transmembrane receptor which is found only in very restricted area in the hindbrain. GFRAL facilitates GDF-15 signaling through Ret receptor tyrosine kinase, similar to GDNF subfamily of growth factors.

Approximately 25% of humans have a missense polymorphism in GDF-15 gene resulting in mutation of histidine 202 to aspartate (histidine 6 in the mature domain), close to the N-terminus of the mature growth factor. This variant is associated with phenotypes in prostate cancer, hyperemesis gravidarum, (severe morning sickness in pregnancy) and rheumatoid arthritis. The underlying mechanism and significance of these associations is still unclear though.

GDF-15 expression in healthy subjects is abundant in placenta, followed by the prostate and very low levels in the bladder, kidney, colon, stomach, liver, gall bladder, pancreas, and endometrium1-3. GDF-15 is expressed by cardiomyocytes, adipocytes, macrophages, endothelial and vascular smooth muscle cells4. High circulating GDF-15 concentration are in general related to inflammation, myocardial ischemia, and cancer except for in pregnancies. It is often induced under stress to maintain cell and tissue homeostasis5-6.

GDF-15 is proposed as a diagnostic biomarker in colorectal7-8, ovarian9, early-stage lung cancer8,10. It is shown to be an accurate marker for differentiating pancreatic adenocarcinoma and chronic pancreatitis11. It has also shown to be a potential biomarker to aid in the discrimination between prostate cancer and benign hyperplasia12-14, studied as a biomarker for disease prognosis and as an emerging target for cancer immunotherapy15. Neutralizing antibodies against GDF-15 has been studied to revert the weight loss in animal models of cancer-related cachexia15-17.

References:
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3. Uhlen M, Fagerberg L, Hallstrom BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Tissue-based map of the human proteome. Science. (2015) 347:1260419. doi: 10.1126/science.1260419.
4. Tsai VWW, Husaini Y, Sainsbury A, Brown DA, Breit SN. The MIC-1/GDF15-GFRAL pathway in energy homeostasis: implications for obesity, cachexia, and other associated diseases. Cell Metab. (2018) 28:353–68. doi: 10.1016/j.cmet.2018.07.018
5. Adela R, Banerjee SK. GDF-15 as a target and biomarker for diabetes and cardiovascular diseases: a translational prospective. J Diabetes Res. (2015) 2015:490842. doi: 10.1155/2015/490842
6. Guenancia C, Kahli A, Laurent G, Hachet O, Malapert G, Grosjean S, et al. Pre-operative growth differentiation factor 15 as a novel biomarker of acute kidney injury after cardiac bypass surgery. Int J Cardiol. (2015) 197:66–71. doi: 10.1016/j.ijcard.2015.06.012.
7. Li C, Wang J, Kong J, Tang J, Wu Y, Xu E, et al. GDF15 promotes EMT and metastasis in colorectal cancer. Oncotarget. (2016) 7:860–72. doi: 10.18632/oncotarget.6205.
8. Wang X, Yang Z, Tian H, Li Y, Li M, Zhao W, et al. Circulating MIC-1/GDF15 is a complementary screening biomarker with CEA and correlates with liver metastasis and poor survival in colorectal cancer. Oncotarget. (2017) 8:24892–901. doi: 10.18632/oncotarget.15279.
9. Zhao D, Wang X, Zhang W. GDF15 predict platinum response during first-line chemotherapy and can act as a complementary diagnostic serum biomarker with CA125 in epithelial ovarian cancer. BMC Cancer. (2018) 18:328. doi: 10.1186/s12885-018-4246-4.
10. Liu YN, Wang XB, Wang T, Zhang C, Zhang KP, Zhi XY, et al. Macrophage inhibitory cytokine-1 as a novel diagnostic and prognostic biomarker in stage I and II nonsmall cell lung cancer. Chin Med J. (2016) 129:2026–32. doi: 10.4103/0366-6999.189052.
11. Hogendorf P, Durczynski A, Skulimowski A, Kumor A, Poznanska G, Strzelczyk J. Growth differentiation factor (GDF-15) concentration combined with Ca125 levels in serum is superior to commonly used cancer biomarkers in differentiation of pancreatic mass. Cancer Biomark. (2018) 21:505–11. doi: 10.3233/CBM-170203.
12. Gronberg H, Adolfsson J, Aly M, Nordstrom T, Wiklund P, Brandberg Y, et al. Prostate cancer screening in men aged 50-69 years (STHLM3): a prospective population-based diagnostic study. Lancet Oncol. (2015) 16:1667–76. doi: 10.1016/S1470-2045(15)00361-7.
13. Li J, Veltri RW, Yuan Z, Christudass CS, Mandecki W. Macrophage inhibitory cytokine 1 biomarker serum immunoassay in combination with PSA is a more specific diagnostic tool for detection of prostate cancer. PLoS ONE. (2015) 10:e0122249. doi: 10.1371/journal.pone.0122249.
14. Bansal N, Kumar D, Gupta A, Chandra D, Sankhwar SN, Mandhani A. Relevance of MIC-1 in the era of PSA as a serum based predictor of prostate cancer: a critical evaluation. Sci Rep. (2017) 7:16824. doi: 10.1038/s41598-017-17207-2.
15. Lerner L, Tao J, Liu Q, Nicoletti R, Feng B, Krieger B, et al. MAP3K11/GDF15 axis is a critical driver of cancer cachexia. J Cachexia Sarcopenia Musc. (2016) 7:467–82. doi: 10.1002/jcsm.12077
16. Chrysovergis K, Wang X, Kosak J, Lee SH, Kim JS, Foley JF, et al. NAG-1/GDF-15 prevents obesity by increasing thermogenesis, lipolysis and oxidative metabolism. Int J Obes. (2014) 38:1555–64. doi: 10.1038/ijo.2014.27
17. Tran T, Yang J, Gardner J, Xiong Y. GDF15 deficiency promotes high fat diet-induced obesity in mice. PLoS ONE. (2018) 13:e0201584. doi: 10.1371/journal.pone.0201584
18. HHS Publication, 5th ed., 2007. Biosafety in Microbiological and Biomedical Laboratories. Available http://www.cdc.gov/biosafety/ publications/bmbl5/BMBL5
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20. Kricka L. Interferences in immunoassays – still a threat. Clin Chem 2000; 46: 1037–1038.

GDF-15

GDF-15 (H Specific) ELISA AL-1018

Calvert ME, Kalra B, Patel A, Kumar A, Shaw ND. Serum and urine profiles of TGF-β superfamily members in reproductive aged women. Clin Chim Acta. 2021 Dec 5;524:96-100. doi: 10.1016/j.cca.2021.12.002. Online ahead of print

All Products Cited: Inhibin A (pico) ELISA AL-184; Inhibin B ELISA AL-107; Inhibin (Total) ELISA AL-134; AMH (PCOCheck) ELISA AL-196; Activin A ELISA AL-110; Activin B ELISA AL-150; Activin AB ELISA AL-153; Follistatin ELISA AL-117; GDF-9/BMP-15 Complex ELISA AL-181; GDF-15 (Total) ELISA AL-1014; GDF-15 (H2O2D non-detectable) ELISA AL-1018

GDF-15 (Total) ELISA AL-1014

Calvert ME, Kalra B, Patel A, Kumar A, Shaw ND. Serum and urine profiles of TGF-β superfamily members in reproductive aged women. Clin Chim Acta. 2021 Dec 5;524:96-100. doi: 10.1016/j.cca.2021.12.002. Online ahead of print

All Products Cited: Inhibin A (pico) ELISA AL-184; Inhibin B ELISA AL-107; Inhibin (Total) ELISA AL-134; AMH (PCOCheck) ELISA AL-196; Activin A ELISA AL-110; Activin B ELISA AL-150; Activin AB ELISA AL-153; Follistatin ELISA AL-117; GDF-9/BMP-15 Complex ELISA AL-181; GDF-15 (Total) ELISA AL-1014; GDF-15 (H2O2D non-detectable) ELISA AL-1018

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