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 ζ (PTPζ), 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 PI3 kinase to ERK, remains to be clarified.
A chemical approach is essential to glycobiology research. The chemically synthesized, pure oligosaccharides and glycoconjugates have been utilized to elucidate the carbohydrate structures and their metabolic pathways for the expression of physiological functions in vivo. In this article, our recent achievements in glycobiology research using synthetic sialyl glycans are reviewed focussing on cellular recognition events, such as viral infection, cell adhesion, and toxin-receptor interaction.
Gangliosides have been shown to modulate various neural activities. However, the molecular mechanisms remain to be clarified. Recent studies show that gangliosides form microdomains at the surface of plasma membrane and are implicated in signal transduction, because a variety of signaling molecules are associated with them. Here, involvement of the microdomain signaling in ganglioside-mediated neural function is discussed.
Some cytokines have a carbohydrate recognition activity which seems to modulate the interaction between cytokines and their receptors in an immune system. In this article, we have given an overview of the studies on cytokine's carbohydrate recognition activity and reviewed the functional roles of IL-2 carbohydrate recognition activity. CTLL-2 cells proliferate dependently on IL-2. Since a high-mannose type glycan with five or six mannosyl residues can inhibit IL-2-dependent cell proliferation and its signal transduction, it was indicated that the high-mannose type glycan functioned as a modulator of IL-2 on T cell proliferation. Since it has been reported that each IL-2 receptor subunit expressed independently shows only weak binding to IL-2, the mechanism by which IL-2 stimulates the formation of a high affinity IL-2-IL-2Rα, -β, or-γ complex remained unclear. However, we found that IL-2 recognizes both the high-mannose type glycan with five or six mannosyl residues on IL-2 receptor α subunit and its specific peptide sequence. The formation of IL-2-IL-2Rα complex via dual recognition may be a trigger to form the high-affinity receptor complex which consists of all constituents required for the cellular signaling.