Roles of proteoglycans in reception of the midkine signal

Midkine (MK) is a heparin-binding growth factor with diverse activities, such as promotion of cell growth, cell survival and cell migration. Pleiotrophin (PTN) / heparin-binding growth-associated molecule (HB-GAM) subsequently identified has sequence similarity to MK, while they are not related to other growth factors. MK promotes growth and the progression of tumor cells and enhances migration of inflammatory cells to participate in neointima formation and renal damages after ischemia. Thus, MK attracts attention as a target molecule to cure diseases. The signaling receptor of MK contains protein tyrosine phosphatase xi (PTPxi), which is a chondroitin sulfate proteoglycan, or syndecans, which are heparan sulfate proteoglycans. MK binds to oversulfated structures in the glycosaminoglycan chains of the proteoglycans, namely chondroitin sulfate E structure and trisulfated structure in heparan sulfate disaccharide units. This binding is necessary for the action of MK. MK is mainly composed of two domains held by disulfide bridges. The more C-terminally located domain has clusters of basic amino acids, which recognize oversulfated region in glycosaminoglycans. The MK receptor also contains a transmembrane glycoprotein, LRP (low density lipoprotein receptor-related protein). The way of interaction of proteoglycans to LRP to transmit the signal to the downstream signaling system, namely P13 kinase to ERK, remains to be clarified.