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 ARTICLESThis 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 Abbreviations ALK, anaplastic lymphoma kinase; Hes-1, hairy and enhancer of split-1; HIF, hypoxia-induced factor; LRP, low-density lipoprotein receptor-related protein; Mdka, Midkine-a; Mdkb, Midkine-b; MK, midkine; PTN, pleiotrophin; PTPζ, receptor protein tyrosine phosphatase Z1

Midkine Is a Novel Regulator of Amphetamine-Induced Striatal Gliosis and Cognitive Impairment: Evidence for a Stimulus-Dependent Regulation of Neuroinflammation by Midkine

“…Overall, the data presented here are relevant because the roles of MK in promoting inflammation had been described in detail in peripheral organs such as kidney and liver [10] but little was known about a possible role of MK in central inflammation. We now demonstrate for the first time that MK is a novel modulator of amphetamine-induced neuroinflammation in a brain area-dependent manner.…”

“…Midkine expression levels in the brain are also upregulated in different pathologies characterized by overt neuroinflammation [3, 10, 20, 38]. Midkine is known to exert neuroprotective effects in some of these pathologies including Alzheimer's disease [18] and brain ischemia [39].…”

“…Inhibition of the phosphatase activity of RPTP β / ζ by MK binding regulates the tyrosine phosphorylation levels of substrates of RPTP β / ζ which are known regulators of neuroinflammatory processes such as TrkA [43]. Signaling pathways downstream of MK/RPTP β / ζ which are also known to participate in gliosis include MAPK pathways [10]. Further studies are needed to test the possible involvement of these signaling pathways in the modulatory actions of MK in neuroinflammation.…”

“…Midkine (MK) is a cytokine with important functions in peripheral inflammatory processes in different pathological conditions [10, 11]. MK facilitates the migration of macrophages and neutrophils [12–14] and prevents differentiation of regulatory T-cells by inhibiting the development of tolerogenic dendritic cells [15, 16].…”

Midkine: In the Middle of the Pathogenesis of Acute Respiratory Distress Syndrome–associated Lung Fibrosis?

“…This is clinically relevant and important because the presence of lung fibrosis in patients with ARDS is associated with high mortality (7,11). The investigators also connected the epithelial-to-mesenchymal transition profile with the midkine and, specifically, the midkine-Notch2-angiotensinconverting enzyme signaling pathway; the role of the latter is emerging in the pathogenesis of a wide range of disorders, including peripheral artery occlusive disease and renal diseases (9).…”