The Midkine Family and Its Receptors

Abstract

Midkine (MK) and pleiotrophin (PTN) comprise a family, the MK family, which is distinct from other growth factor families. The MK family is evolutionally conserved, and it is studied in a variety of animals. The C-terminal domain of MK contains cluster I, a cluster of basic amino acids. Cluster I is important for binding to heparin and chondroitin sulfate. The MK family members strongly bind to Syndecan (a heparan sulfate proteoglycan) and PTPζ (a chondroitin sulfate proteoglycan and a protein tyrosine phosphatase). Chondroitinase treatment of PTPζ, a mutation in cluster I of MK, or chondroitin sulfate E signifi cantly suppresses cell migration mediated via MK and PTPζ. It is also known that the MK family members bind to anaplastic lymphoma kinase (ALK), LDL receptor-related protein (LRP), integrin α4β and integrin α6β1. Thus, it is thought that a receptor complex involving integrin, LRP and PTPζ mediates the signals of the MK family. The MK family plays important roles in (1) the nervous system (injury, etc.), (2) cancer, and infl ammation (nephritis, vascular diseases, rheumatoid arthritis, etc.). Therefore, studies on the MK family will contribute to understanding of the pathogenesis of and to development of therapeutic strategies for these diseases. As mentioned above, E type chondroitin sulfate suppresses MK-mediated cell migration, suggesting that sugars are candidate therapeutics if MK is a molecular target for the therapy for a disease. In addition, a soluble fragment of a receptor could specifi cally block the functions of the MK family. Studies on the MK family may also contribute to elucidation of the action mechanisms of functional sugar chains. For example, cluster I of MK is localized at a particular site, i.e., not exposed to the opposite site. Therefore, it is interesting what the function of the opposite site is. In addition, the MK family members bind to two glycosaminoglycans, i.e., heparan sulfate and chondroitin sulfate. It remains unknown whether this differential binding has different biological signifi cance. Studies on the MK family may shed light on the biological roles of glycosaminoglycans.