Midkine (MK), also known as neurite growth-promoting factor 2 (NEGF2), is a 13kDa heparin-binding growth factor or cytokine composed of two domains: The N-terminally located N-domain and the C-terminally located C-domain, which are connected by a hinge. The C-domain plays a role in neuronal development, whereas the N-domain is important for protein stability and dimerization. MK is involved in development, reproduction, repair, inflammation, innate immunity, control of blood pressure and angiogenesis.

MK is strongly expressed during embryogenesis and due to its distribution in the embryo it has been proposed to play a role in neurogenesis, epithelial-mesenchymal interactions and mesoderm remodeling. Expression in adult tissues is restricted to the kidney, epidermis, bronchial epithelium, lymphocytes and macrophages, but it is strongly expressed in the brain, kidney, blood vessels and heart after tissue injury as well as during inflammation, infection and oncogenesis. During inflammation, substratum-bound MK enhances neutrophil and macrophage migration directly and through induction of chemokine expression. On the other hand, soluble MK is associated with differentiation of regulatory T-cells, induction of epithelial-mesenchymal transition, angiogenesis, fibrinolytic and anti-microbial activity.

MK signaling is mediated by cell surface receptors as well as membrane proteins such as Protein Tyrosine Phosphatase ζ (PTPζ), low density lipoprotein receptor-related proteins (LRP), Notch2, integrins, anaplastic lymphoma kinase (ALK) and neuroglycan C. Binding of MK to PTPζ induces tyrosine phosphorylation in β-catenin and Wnt signaling inhibition. Furthermore it induces phosphorylation of PI3K, MAPK, PKC and Src family kinase. Binding of MK to LRP leads to embryonic neuronal survival and prevention of hypoxic injury via Akt and HIF1α. Binding of MK to integrins activates focal adhesion kinase, paxillin and STAT1α pathway leading to increase invasiveness of cancer cells. Activation of ALK by MK leads to phosphorylation of IRS-1, MAPK, PI3K and activation of NF-κB.

Due to its multifunctionality, MK has become an emerging target of drug development for the treatment of multiple diseases. On the one hand, administration of MK ameliorates ischemic injury, enhances oocyte maturation and promotes neurogenesis therefore limiting the progression of neurodegenerative diseases. However on the other hand, due to its over-expression in malignant tumors and in inflammation, MK inhibitors may be useful in the treatment of cancer, multiple sclerosis, hypertension and osteoporosis.

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