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the treatment or prevention of inflammatory diseases.


[Prevention of cell death using midkine]

Midkine has anti-apoptotic activity; the effect is best illustrated using embryonic neurons as target cells. Rentinal photoreceptor cells die after exposure to constant light in rats. Prior injection of midkine to the retina prevents the cell death. Temporary brain ischemia in gerbils leads to delayed neuronal death in the hippocampus. Prior delivery of midkine to the ventricle retards this process.

Midkine is heavily deposited in senile plaques of patients with Alzheimerﾕs disease. Midkine binds to amyloid b-peptide and suppresses the cytotoxic activity. There is a possibility that midkine is produced to counteract the toxicity of amyloid β-peptide. Midkine enhances the survival of bovine embryos cultured in vitro. Furthermore, midkine suppresses infection of HIV in target cells.

The anti-apoptotic and cell-protecting activites make midkine a promising therapeutic. However, the proinflammatory activity and protective activity of midkine should be carefully evaluated in each case.


[Essentials of midkine]

Protein
Midkine is a basic protein, essentialy composed of two domains held together by disulfide linkages. Each domain contains three anti-paralel b-sheets (Fig. 3).

Fig. 3

The domain organization of midkine and three dimensional structure of the domains. Two heparin-binding sites in the C-domain are encircled. Cited from Muramatsu, T., J. Biochem. 132, 359-371 (2002); Wiley Encyclopedia Mol. Med. pp2086-2088 (2002) [・2002, John Wiley & Sons]. This material is used by permission of John Wiley & Sons, Inc.

The more C-terminally located domain is usually responsible for midkine activity. Midkine is dimerized through the action of transglutaminase. Some midkine activity requires this dimerization. Pleiotrophin［also called HB-GAM (heparin-binding growth-associeted molecule)］has 45 % sequence identity with midkine (Fig. 4).

Fig.4

Protein structure of human midkine (MK). Amino acids conserved with pleiotrophin (PTN) are boxed. S-S linkages are shown by lines. Arrowheads show exon boundaries. Amino acids conserved also in Drosophila miple are shaded. Cited from Muramatsu, T., J. Biochem., 132, 359-371 (2002)

Midkine has been found in all vertebrata examined, namely from human to zebrafish. Zebrafish has two species of midkine. Although Drosophila lacks midkine, miple, and miple 2 molecules with repeating units homologous to the C-terminal half of both the midkine and pleiotrophin are present.

Gene
The human midkine gene is present in chromosome 11 band p.11.2, and is flanked by DGKz (diacyglycerokinase z gene) and CHRM4 (muscarnic acetylcholine receptor 4 gene) (Fig.5).

Fig.5

Structure of the human midkine gene (MDK). For comparison, the human pleiotrophin gene (PTN) is also shown. <,exon, RARE, retinoic acid responsive element; WT1, binding site for WT1 protein. cited from Muramatsu, T., J. Biochem. 132, 359-371 (2002)

The symbol for the human midkine gene is MDK. The mouse midkine gene (Mdk) is present on chromosome 2. In the upsteam of MDK, there is a retinoic acid responsive element, and midkine gene expression is induced by retinoic acid. Furthermore, the upstream region has a binding site for Wilmsﾕ tumor suppressor WT1. When the function of WT1 is lost, suppression does not take place, and midkine comes to be expressed. Although the pleiotrophin gene is located in a broader region of the human genome, the fundamental structure is similar.

Function and action mechanisms
Midkine is most strongly expressed in midgestation. Epithelial tissues involved in epithelial mesenchymal interactions, nervous tissues during differentiation and mesenchymal tissues undergoing remodeling are the principal sites of expression. In the adult, midkine expression is restricted. Endothelial cells of blood vessels and mucus epithelium of certain organs are important sites of expression. When a tissue is injured, midkine expression is increased or newly induced. Midkine promotes the survival and migration of various cells, and also has many other activities ( Table 1). Using a blood vessel model, in which endothelial cells are layered on gels with smooth muscle cells, the complex mode of midkine action during epithelial mesenchymal interactions has been clarified (Fig. 6).

Fig.6

The action mechanism of midkine in epithelial mesenchymal interactions.

Among midkine receptors, receptor-type protein tyrosine phophafase z (PTP z) has been studied extensively. Midkine binds to the chondroitin sulfate portion with high affinity and to the protein portion with low affinity. In addition, low density lipoprotein receptor-related protein (LRP) and anaplastic leukemia kinase (ALK) have also been identified as receptors. Syndecans, a family of transmembrane heparan sulfate proteoglycans, can also participate in midkine signaling. The midkine receptor is considered to be a molecular complex containing these proteins. Very recently, integrins have been found as components of the receptor. The downstream signaling system contains PI3 kinase followed by ERK (Fig.7).

Fig.7

The signal receptor complex of midkine (MK) and the downstream signaling system. Cited from Muramatsu, T., J. Biochem., 132, 359-371 (2002)

Midkine binds to the oversulfated portion of heparan sulfate and chondroitin sulfate. The structure is shown in Fig. 8

Fig.8

Carbohydrate structure required for strong binding to midkine. The Trisulfated structure in heparan sulfate and chondroitin sulfate E structure are shown.

Midkine is also incorporated into the cell and translocated to the nuclers. The survival promoting activity requires the nuclear translocation. LRP is involved in the uptake and nuclelin or laminin-binding protein precursor participates in the nuclear translocation.


[Further information]

More detailed information is available through reading review articles or visiting other home pages. The following are recommended.
1. Muramatsu, T. (2002) Midkine and pleiotrophin: two related proteins involved in development, survival, inflammation and tumorigenesis. J. Biochem 132, 359-371. ［http://jb.oxfordjournals.org/cgi/reprint/132/3/359］

2. Muramatsu, T. (2002) Midkine in Wiley Encyclopedia of Molecular Medicine pp2086-2088. John Wiley & Sons., Inc. New York, USA

3. Muramatsu, T. Chondroitin sulfate E in signaling of the growth factor midkine.　［http://www.glycoforum.gr.jp/science/glycogenes/09/09E.html］

4. Kurtz, A., Schulte, A. M., and Wellstein, A. (1995) Pleiotrophin and midkine in normal development and tumor biology. Crit. Rev. Oncol. 6, 151-177

5. Locus link (http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=4192)

6. Kadomatsu, K., and Muramatsu, T. (2004) Midkine and pleiotrophin in neural development and cancer. Cancer Lett. 204, 127-143.

7. Muramatsu T, Muramatsu H, Kaneda N, Sugahara K. (2003) Recognition of glycosaminoglycans by midkine. Methods Enzymol. 363, 365-376.

It is also possible to read original articles listed in Original articles as references. By searching Pub Med [http://www.ncbi.nlm.nih.gov/PubMed/] using midkine as a key word, more articles become available. The summary of an article listed in Original articles as references can be accessed using the PMID number written at the end of each reference.