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Midkine is a 13-kDa heparin-binding growth factor with 45% sequence identity to pleiotrophin. Pleiotrophin has been demonstrated to bind to protein-tyrosine phosphatase ζ (PTPζ) with high affinity. In this study, we examined the binding of midkine to PTPζ by solid-phase binding assay. Midkine and pleiotrophin binding to PTPζ were equally inhibited by soluble pleiotrophin and also by some specific glycosaminoglycans. For both bindings, Scatchard analysis revealed low (3.0 nm) and high (0.58 nm) affinity binding sites. These results suggested that PTPζ is a common receptor for midkine and pleiotrophin. Midkine is structurally divided into the N- and C-terminal halves, and the latter exhibited full activity for PTPζ binding and neuronal migration induction. The C-terminal half contains two heparin-binding sites consisting of clusters of basic amino acids, Clusters I and II. A mutation at Arg⁷⁸ in Cluster I resulted in loss …