Receptor structure and inhibition of midkine, a growth factor controled by retinoic acid

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We studied on structure and function of midkine (MK). Chemically synthesized C-terminal half molecule of MK has neurite outgrowth promoting activity and heparin binding activity. A mutant MK whose putative heparin binding sites were altered by in vitro mutagenesis lost neurite promoting activity, indicating that heparing binding activity correlates with neurite promoting activity. Structural requirements for binding to MK was analyzed by chemically modified heparing and heparin-derived oligosaccharides. All of sulfate groups (2-0,6-0,2-N) were required for inhibition of neurite promoting activity. The size of heparin oligosaccharide necessary for the inhibition was about 20-mer. On the other hand, a putative MK receptor was disclosed by analysis of membrane proteins binding to MK column. A histochemical method to localize the MK receptor of protein nature was also established. We also obtained results indicating the correlation of MK expression and cancer, brain and heart infarction and rheumatoid arthritis. A sensitive method to determine MK levels was also devised, enabling MK assay in serum samples.