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Midkine (MK) and pleiotrophin (PTN) are low molecular weight proteins with closely related structures. They are mainly composed of two domains held by disulfide bridges, and there are three antiparallel β-sheets in each domain. MK and PTN promote the growth, survival, and migration of various cells, and play roles in neurogenesis and epithelial mesenchymal interactions during organogenesis. A chondroitin sulfate proteoglycan, protein-tyrosine phosphatase ζ (PTPζ), is a receptor for MK and PTN. The downstream signaling system includes ERK and P13 kinase. MK binds to the chondroitin sulfate portion of PTPζ with high affinity. Among the various chondroitin sulfate structures, the E unit which has 4, 6-disulfated N-acetylgalactosamine, provides the strongest binding site. The expression of MK and PTN is increased in various human tumors, making them promising as tumor markers and as targets for …