Alternative titles; symbols
HGNC Approved Gene Symbol: MDK
Cytogenetic location: 11p11.2 Genomic coordinates (GRCh38) : 11:46,380,784-46,383,837 (from NCBI)
Midkine is a retinoic acid-responsive, heparin-binding growth factor expressed in various cell types during embryogenesis. It promotes angiogenesis, cell growth, and cell migration. Midkine is also expressed in several carcinomas, suggesting that it may play a role in tumorigenesis, perhaps through its effects on angiogenesis (summary by Reynolds et al., 2004).
Using mouse Mk to screen a midgestation human embryonic kidney cDNA library, followed by screening a placenta genomic library, Tsutsui et al. (1991) cloned human MDK, which they called MK. The deduced 121-amino acid protein has a signal sequence and shares 87% identity with mouse Mk. Orthologs of MK were detected in rat, cow, and chicken. The chicken ortholog, Rihb, is a retinoic acid-induced heparin-binding protein. MK shares about 50% amino acid homology with the human heparin-binding protein pleiotrophin (PTN; 162095), with highest conservation in the central part of the molecule and complete conservation of cysteine residues. Northern blot analysis detected a transcript of about 1 kb in adult human kidney and PA1 human teratocarcinoma cells.
Using affinity chromatography, Kurosawa et al. (2001) showed that midkine bound rat glypican-2 (GPC2; 618446). Binding was mainly through the heparan sulfate chains of Gpc2, as the binding affinity between midkine and the Gpc2 core protein was low. Microbeads coated with midkine induced clustering of Gpc2 in transfected COS cells, and binding of midkine to cell-surface Gpc2 induced adhesion and neurite outgrowth in rat N2a neuroblastoma cells.
Reynolds et al. (2004) found that hypoxia induced midkine expression in alveolar epithelial cells and pulmonary vasculature in a strain of mice sensitive to hypoxia. Hypoxia induced expression of both HIF1-alpha (603348) and midkine in human placental adenocarcinoma, mouse fetal lung mesenchyme, and human pulmonary adenocarcinoma cell lines. HIF1-alpha induced midkine expression via regulatory elements in the mouse midkine promoter. Chronic expression of midkine during embryonic development in transgenic mice resulted in pulmonary arterial remodeling and muscularization, but only during the postnatal phase of lung development. In fetal mouse lung mesenchymal cells and transgenic mice, midkine upregulated expression of myocardin (MYOCD; 606127), a regulator of smooth muscle cell differentiation.
Intraperitoneal adhesions between organs or between organs and peritoneal walls occur in more than 90% of cases involving major abdominal operations. Using a model of postoperative adhesions and Mk-null mice, Inoh et al. (2004) showed that midkine was fundamentally involved in the formation of intraperitoneal adhesions, at least partly by promoting migration of macrophages and neutrophils to the omentum.
Hobo et al. (2009) found that 5/6 nephrectomy in mice, a model of chronic kidney disease, induced expression of midkine in lung, leading to elevated angiotensin-converting enzyme (ACE; 106180) activity and plasma angiotensin II (106150) levels and subsequent hypertension. Exposure to midkine enhanced ACE expression in primary cultured human lung microvascular endothelial cells. Oxidative stress may have contributed to midkine expression, since 5/6 nephrectomy induced expression of NADH/NADPH oxidase-1 (NOX1; 300225), Nox2 (CYBB; 300481), and Nox4 (605261). Furthermore, an antioxidant reduced midkine expression and plasma angiotensin II levels and ameliorated hypertension in 5/6 nephrectomized mice.
Uehara et al. (1992) determined that the MDK gene contains 4 exons. The 5-prime flanking region adjacent to the start site contains 5 GC boxes, a steroid/thyroid hormone receptor-binding site, and an A/T-rich island, but there is no obvious CAAT box. Further upstream there is a region with high GC content. The mouse Mdk gene has a similar organization, with conservation of exons and significant homology in the 5-prime region adjacent to the start site. There are 3 additional regions of homology between mouse and human MDK in the 5-prime UTR.
By study of somatic cell hybrids, Eddy et al. (1991) demonstrated that the MDK gene segregates concordantly with chromosome 11 and, using cell hybrids carrying translocations involving chromosome 11, they mapped the gene regionally to 11p13-p11. Kaname et al. (1993) mapped the MDK gene to human chromosome 11p11.2 by fluorescence in situ hybridization. Simon-Chazottes et al. (1992) mapped the mouse Mdk gene to chromosome 2, using an interspecific backcross panel and microsatellite polymorphisms as markers. O'Hara et al. (1995) used somatic cell hybrid analysis and interspecific backcross analysis, respectively, to map human Mdk to chromosome 11p13-p11 and mouse Mdk to a syntenic region of mouse chromosome 2. They also mapped an Mdk pseudogene to mouse chromosome 11.
Using microarray analysis, Ezquerra et al. (2005) found that aortae of Mk -/- mice showed elevated expression of renin (REN; 179820), angiotensinogen (106150), angiotensin II receptor-1 (AGTR1; 106165), and angiotensin II receptor-2 (AGTR2; 300034) and decreased expression of Ace.
Eddy, R. L., Kretschmer, P. J., Fairhurst, J. L., Shows, T. B., Bohlen, P., O'Hara, B., Kovesdi, I. A human gene family of neurite outgrowth-promoting proteins: heparin-binding neurite outgrowth promoting factor maps to 11p11-11p13. (Abstract) Cytogenet. Cell Genet. 58: 1958 only, 1991.
Ezquerra, L., Herradon, G., Nguyen, T., Silos-Santiago, I., Deuel, T. F. Midkine, a newly discovered regulator of the renin-angiotensin pathway in mouse aorta: significance of the pleiotrophin/midkine developmental gene family in angiotensin II signaling. Biochem. Biophys. Res. Commun. 333: 636-643, 2005. [PubMed: 15979460] [Full Text: https://doi.org/10.1016/j.bbrc.2005.05.113]
Hobo, A., Yuzawa, Y., Kosugi, T., Kato, N., Asai, N., Sato, W., Maruyama, S., Ito, Y., Kobori, H., Ikematsu, S., Nishiyama, A., Matsuo, S., Kadomatsu, K. The growth factor midkine regulates the renin-angiotensin system in mice. J. Clin. Invest. 119: 1616-1625, 2009. [PubMed: 19451697] [Full Text: https://doi.org/10.1172/JCI37249]
Inoh, K., Muramatsu, H., Ochiai, K., Torii, S., Muramatsu, T. Midkine, a heparin-binding cytokine, plays key roles in intraperitoneal adhesions. Biochem. Biophys. Res. Commun. 317: 108-113, 2004. [PubMed: 15047154] [Full Text: https://doi.org/10.1016/j.bbrc.2004.03.015]
Kaname, T., Kuwano, A., Murano, I., Uehara, K., Muramatsu, T., Kajii, T. Midkine gene (MDK), a gene for prenatal differentiation and neuroregulation, maps to band 11p11.2 by fluorescence in situ hybridization. Genomics 17: 514-515, 1993. [PubMed: 8406506] [Full Text: https://doi.org/10.1006/geno.1993.1359]
Kurosawa, N., Chen, G.-Y., Kadomatsu, K., Ikematsu, S., Sakuma, S., Muramatsu, T. Glypican-2 binds to midkine: the role of glypican-2 in neuronal cell adhesion and neurite outgrowth. Glycoconj. J. 18: 499-507, 2001. [PubMed: 12084985] [Full Text: https://doi.org/10.1023/a:1016042303253]
O'Hara, B., Jenkins, N. A., Gilbert, D. J., Copeland, N. G., Shows, T. B., Eddy, R. L., Bohlen, P., Kovesdi, I. Chromosomal assignment of the heparin-binding cytokine genes MDK and PTN in mouse and man. Cytogenet. Cell Genet. 69: 40-43, 1995. [PubMed: 7835084] [Full Text: https://doi.org/10.1159/000133934]
Reynolds, P. R., Mucenski, M. L., Le Cras, T. D., Nichols, W. C., Whitsett, J. A. Midkine is regulated by hypoxia and causes pulmonary vascular remodeling. J. Biol. Chem. 279: 37124-37132, 2004. [PubMed: 15197188] [Full Text: https://doi.org/10.1074/jbc.M405254200]
Simon-Chazottes, D., Matsubara, S., Miyauchi, T., Muramatsu, T., Guenet, J.-L. Chromosomal localization of two cell surface-associated molecules of potential importance in development: midkine (Mdk) and basigin (Bsg). Mammalian Genome 2: 269-271, 1992. [PubMed: 1347477] [Full Text: https://doi.org/10.1007/BF00355437]
Tsutsui, J., Uehara, K., Kadomatsu, K., Matsubara, S., Muramatsu, T. A new family of heparin-binding factors: strong conservation of midkine (MK) sequences between the human and the mouse. Biochem. Biophys. Res. Commun. 176: 792-797, 1991. [PubMed: 2025291] [Full Text: https://doi.org/10.1016/s0006-291x(05)80255-4]
Uehara, K., Matsubara, S., Kadomatsu, K., Tsutsui, J., Muramatsu, T. Genomic structure of human midkine (MK), a retinoic acid-responsive growth/differentiation factor. J. Biochem. 111: 563-567, 1992. [PubMed: 1639750] [Full Text: https://doi.org/10.1093/oxfordjournals.jbchem.a123797]