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Structure and function of midkine as the basis of its pharmacological effects
Author(s) -
Muramatsu T
Publication year - 2014
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12353
Subject(s) - pleiotrophin , midkine , biology , microbiology and biotechnology , protein tyrosine phosphatase , receptor tyrosine kinase , receptor , autocrine signalling , cytokine , signal transduction , transmembrane protein , cell surface receptor , growth factor , cancer research , biochemistry , immunology
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.