Structure and function of midkine as the basis of its pharmacological effects

Abstract

Midkine (MK) is a heparin-binding growth factor or cytokine and forms a small protein family, the other member of which is pleiotrophin. MK enhances survival, migration, cytokine expression, differentiation and other activities of target cells. MK is involved in various physiological processes, such as development, reproduction and repair, and also plays important roles in the pathogenesis of inflammatory and malignant diseases. MK is largely composed of two domains, namely a more N-terminally located N-domain and a more C-terminally located C-domain. Both domains are basically composed of three antiparallel β-sheets. In addition, there are short tails in the N-terminal and C-terminal sides and a hinge connecting the two domains. Several membrane proteins have been identified as MK receptors: receptor protein tyrosine phosphatase Z1 (PTPζ), low-density lipoprotein receptor-related protein, integrins, neuroglycan C, anaplastic lymphoma kinase and Notch-2. Among them, the most established one is PTPζ. It is a transmembrane tyrosine phophatase with chondroitin sulfate, which is essential for high-affinity binding with MK. PI3K and MAPK play important roles in the downstream signalling system of MK, while transcription factors affected by MK signalling include NF-κB, Hes-1 and STATs. Because of the involvement of MK in various physiological and pathological processes, MK itself as well as pharmaceuticals targeting MK and its signalling system are expected to be valuable for the treatment of numerous diseases.

Linked articles: This article is part of a themed section on Midkine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-4.

Keywords: Notch-2; anaplastic lymphoma kinase; low-density lipoprotein receptor-related protein 1; midkine; pleiotrophin; receptor protein tyrosine phosphatase Z1.

Figure 1

Structure of human MK and PTN. Amino acids shared by them are shaded, and disulfide bridges are shown by solid lines.

Figure 2

Schematic drawing of MK and its segments.

Figure 3

Schematic illustration of the steric structure of MK C-domain. Long boxes are emphasized portions of β-sheets as illustrated in the protein structure database (http://www.ncbi.nlm.nih.gov/structure/mn).

Figure 4

Genomic organization of the human midkine gene (MDK). Coding exons are shown by closed boxes, and non-coding exons are shown by open or grey boxes. There are five different structures in the upstream non-coding exons in MK mRNA. When a portion of an exon is shared by different structures, the boundaries are shown by dotted vertical lines. The full information on all MK mRNA isoforms is available (http://www.ncbi.nlm.nih.gov/gene/4192). The first exon shared by three isoforms is shown by a grey box. DGKZ, diacylglycerol kinase ζ gene; CHRM4, muscarinic cholinergic receptor 4 gene; closed star, a retinoic acid responsive element; open star, a binding site for NF-κB; open hexagon, a binding site for the product of Wilms' tumour suppressor gene.