Haptotactic migration induced by midkine. Involvement of protein-tyrosine phosphatase zeta. Mitogen-activated protein kinase, and phosphatidylinositol 3-kinase.
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 PTPzeta, 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 PTPzeta and PI3-kinase. These results indicate that PTPzeta 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.
Qi
M
M
Department of Biochemistry, Nagoya University School of Medicine, Nagoya 466-8550, Japan.
Ikematsu
S
S
Maeda
N
N
Ichihara-Tanaka
K
K
Sakuma
S
S
Noda
M
M
Muramatsu
T
T
Kadomatsu
K
K
D000818:Animals; D000077214:Becaplermin; D001921:Brain / Q000378:metabolism*; D002352:Carrier Proteins / Q000494:pharmacology*; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002810:Chondroitinases and Chondroitin Lyases / Q000378:metabolism; D003094:Collagen / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology; D004357:Drug Synergism; D004789:Enzyme Activation; D006025:Glycosaminoglycans / Q000494:pharmacology; D000078792:Midkine; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
D002352:Carrier Proteins; D016207:Cytokines; D006025:Glycosaminoglycans; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; C066845:pleiotrophin; D000078792:Midkine; D000077214:Becaplermin; D003094:Collagen; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases; D017027:Protein Tyrosine Phosphatases; C516897:Ptprz1 protein, rat; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5; D002810:Chondroitinases and Chondroitin Lyases