Haptotactic Migration Induced by Midkine

Abstract

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 midkineinduced 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.

ANGPTL3 Stimulates Endothelial Cell Adhesion and Migration via Integrin αvβ3 and Induces Blood Vessel Formation in Vivo

“…Such induction of endothelial cell migration was most prominently detected when recombinant protein was coated to the membrane surface and to a lesser extent when the protein was added to the medium (data not shown). This is a characteristic feature of proteins exerting their effect in a haptotactic manner (33). The migratory response of HMVE cells was abolished by the presence of an antagonistic antibody to ␣ v ␤ 3 but not by the control functionblocking antibody targeting ␣ v ␤ 5 of the same isotype (Fig.…”

Domain Structure of Chondroitin Sulfate E Octasaccharides Binding to Type V Collagen

“…The average molecular weight of oligosaccharide number 2 was 2015.2, which corresponded to an octasaccharide with six sulfate residues, (HexA) 4 (HexNAc) 4 (OSO 3 H) 6 . HPLC analysis of the chondroitinase AC-II digest of number 2 after derivatization with PA showed PA derivatives of Di-diS E , ⌬Di-0S, and ⌬Di-diS E in a molar ratio of 1.0:0.9:1.9 (Table II).…”

“…It is known that its carbohydrate chain, chondroitin sulfate (ChS), 1 has various important biological activities in areas such as cell migration, recognition, and morphogenesis (1)(2)(3)(4)(5). Recently, greater attention has been directed toward the functions of ChS in the brain, optic nerves, and chondrocytes (6 -8).…”

Functional Analysis of the Chondroitin 6-Sulfotransferase Gene in Relation to Lymphocyte Subpopulations, Brain Development, and Oversulfated Chondroitin Sulfates

“…Chondroitin sulfate chains also play critical roles in lymphocyte-endothelial cell interactions (11) and enhancing stimulation of T cell responses (12). Furthermore, chondroitin sulfate proteoglycans bearing chondroitin sulfate D or E bind to a growth factor, midkine (13)(14)(15)(16), and chemokines (17), and have been suggested to participate in signaling or modulation of the activities of these factors. However, the in vivo function of chondroitin sulfate has not been clarified directly.…”