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J. Biol. Chem., Vol. 276, Issue 19, 15868-15875, May 11, 2001

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Haptotactic Migration Induced by Midkine
INVOLVEMENT OF PROTEIN-TYROSINE PHOSPHATASE , MITOGEN-ACTIVATED PROTEIN KINASE, AND PHOSPHATIDYLINOSITOL 3-KINASE^*

Maosong Qi, Shinya Ikematsu^§, Nobuaki Maeda^¶, Keiko Ichihara-Tanaka, Sadatoshi Sakuma^§, Masaharu Noda^¶, Takashi Muramatsu, and Kenji Kadomatsu

From the  Department of Biochemistry, Nagoya University School of Medicine, Nagoya 466-8550, the ^§ Pharmaceuticals Development Department, Meiji Milk Products Co., Ltd., 540 Naruda, Odawara 250-0862, and the ^¶ Division of Molecular Neurobiology, National Institute for Basic Biology, Okazaki 444-8585, Japan

Midkine, a heparin-binding growth factor, plays a critical role in cell migration causing suppression of neointima formation in midkine-deficient mice. Here we have determined the molecules essential for midkine-induced migration. Midkine induced haptotaxis of osteoblast-like cells, which was abrogated by the soluble form of midkine or pleiotrophin, a midkine-homologous protein. Chondroitin sulfate B, E, chondroitinase ABC, B, and orthovanadate, an inhibitor of protein-tyrosine phosphatase, suppressed the migration. Supporting these data, the cells examined expressed PTP, a receptor-type protein-tyrosine phosphatase that exhibits high affinity to both midkine and pleiotrophin and harbors chondroitin sulfate chains. Furthermore, strong synergism between midkine and platelet-derived growth factor in migration was detected. The use of specific inhibitors demonstrated that mitogen-activated protein (MAP) kinase and protein-tyrosine phosphatase were involved in midkine-induced haptotaxis but not PDGF-induced chemotaxis, whereas phosphatidylinositol 3 (PI3)-kinase and protein kinase C were involved in both functions. Midkine activated both PI3-kinase and MAP kinases, the latter activation was blocked by a PI3-kinase inhibitor. Midkine further recruited PTP and PI3-kinase. These results indicate that PTP and concerted signaling involving PI3-kinase and MAP kinase are required for midkine-induced migration and demonstrate for the first time the synergism between midkine and platelet-derived growth factor in cell migration.

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