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Haptotactic Migration Induced by Midkine

INVOLVEMENT OF PROTEIN-TYROSINE PHOSPHATASE ζ, MITOGEN-ACTIVATED PROTEIN KINASE, AND PHOSPHATIDYLINOSITOL 3-KINASE*
Open AccessPublished:May 11, 2001DOI:https://doi.org/10.1074/jbc.M005911200
      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 PTPζ, 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 PTPζ and PI3-kinase. These results indicate that PTPζ 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.
      PI3-kinase
      phosphatidylinositol 3-kinase
      MAP
      mitogen-activated protein
      MK
      midkine
      PTN
      pleiotrophin
      HB-GAM
      heparin-binding growth-associated molecule
      PDGF-BB
      platelet-derived growth factor BB
      PTPζ
      protein-tyrosine phosphatase ζ
      PLL
      poly-l-lysine
      RT-PCR
      reverse transcriptase-polymerase chain reaction
      Cell migration plays a key role in a wide variety of biological phenomena (
      • Lauffenburger D.A.
      • Horwitz A.F.
      ,
      • Sanchez-Madrid F.
      • del Pozo M.A.
      ). There are three main types of cell migration: chemokinesis, chemotaxis, and haptotaxis. Chemokinesis comprises random, non-directional motility in response to a ligand without any orienting cues. Chemotaxis is the cell movement toward a positive gradient of soluble stimulants such as chemokines and growth factors. Haptotaxis involves cell crawling toward substrate-bound molecules such as various extracellular matrix proteins. Cell migration is the result of a series of complicated, integrated processes and is controlled by many kinds of intracellular molecules (
      • Lauffenburger D.A.
      • Horwitz A.F.
      ,
      • Sanchez-Madrid F.
      • del Pozo M.A.
      ). These molecules include Rho small G protein family members, PI3-kinases,1 MAP kinases (Erk1 and Erk2), and protein kinase C.
      Midkine (MK) was first identified as the product of a retinoic acid-responsive gene in embryonal carcinoma cells (
      • Kadomatsu K.
      • Tomomura M.
      • Muramatsu T.
      ,
      • Tomomura M.
      • Kadomatsu K.
      • Nakamoto M.
      • Muramatsu H.
      • Kondoh H.
      • Imagawa K.
      • Muramatsu T.
      ). MK and pleiotrophin (PTN, also called HB-GAM for heparin-binding growth-associated molecule) comprise a family of heparin-binding growth/differentiation factors and are not related to other heparin-binding growth factors such as fibroblast growth factor or hepatocyte growth factor (
      • Li Y.S.
      • Milner P.G.
      • Chauhan A.K.
      • Watson M.A.
      • Hoffman R.M.
      • Kodner C.M.
      • Milbrandt J.
      • Deuel T.F.
      ,
      • Merenmies J.
      • Rauvala H.
      ,
      • Muramatsu T.
      ). MK has been reported to promote neuronal survival and neurite outgrowth (
      • Muramatsu H.
      • Shirahama H.
      • Yonezawa S.
      • Maruta H.
      • Muramatsu T.
      ,
      • Kaneda N.
      • Talukder A.H.
      • Nishiyama H.
      • Koizumi S.
      • Muramatsu T.
      ) and to play roles in carcinogenesis (
      • Choudhuri R.
      • Zhang H.T.
      • Donnini S.
      • Ziche M.
      • Bicknell R.
      ,
      • Kadomatsu K.
      • Hagihara M.
      • Akhter S.
      • Fan Q.W.
      • Muramatsu H.
      • Muramatsu T.
      ) and tissue remodeling (
      • Yoshida Y.
      • Goto M.
      • Tsutsui J.
      • Ozawa M.
      • Sato E.
      • Osame M.
      • Muramatsu T.
      ,
      • Ohta S.
      • Muramatsu H.
      • Senda T.
      • Zou K.
      • Iwata H.
      • Muramatsu T.
      ).
      Using MK knock-out mice, it was demonstrated that MK is involved in neointima formation in a model of restenosis after angioplasty (
      • Horiba M.
      • Kadomatsu K.
      • Nakamura E.
      • Muramatsu H.
      • Ikematsu S.
      • Sakuma S.
      • Hayashi K.
      • Yuzawa Y.
      • Matsuo S.
      • Kuzuya M.
      • Kaname T.
      • Hirai M.
      • Saito H.
      • Muramatsu T.
      ). Neointima is the basic lesion in both atherosclerosis and restenosis after angioplasty (
      • Ross R.
      ). A variety of stresses to the arterial endothelium can induce the migration of smooth muscle cells from the media into the space between the endothelium and internal elastic lamina to form a neointima. One of the most important molecules in this process is PDGF-BB, which is responsible for the migration of smooth muscle cells (
      • Ferns G.A.
      • Raines E.W.
      • Sprugel K.H.
      • Motani A.S.
      • Reidy M.A.
      • Ross R.
      ). Macrophages recruited into the arterial wall also play a critical role in this lesion formation (
      • Boring L.
      • Gosling J.
      • Cleary M.
      • Charo I.F.
      ). Neointima formation and macrophage recruitment to the arterial wall were suppressed in MK-deficient mice (
      • Horiba M.
      • Kadomatsu K.
      • Nakamura E.
      • Muramatsu H.
      • Ikematsu S.
      • Sakuma S.
      • Hayashi K.
      • Yuzawa Y.
      • Matsuo S.
      • Kuzuya M.
      • Kaname T.
      • Hirai M.
      • Saito H.
      • Muramatsu T.
      ). Because MK induces the migration of both smooth muscle cells and macrophages in vitro (
      • Horiba M.
      • Kadomatsu K.
      • Nakamura E.
      • Muramatsu H.
      • Ikematsu S.
      • Sakuma S.
      • Hayashi K.
      • Yuzawa Y.
      • Matsuo S.
      • Kuzuya M.
      • Kaname T.
      • Hirai M.
      • Saito H.
      • Muramatsu T.
      ), it was concluded that the cell migration-inducing activity of MK is crucial for the suppression of neointima formation.
      These findings also suggest a possible interaction between MK and PDGF in smooth muscle cell migration. In addition, remodeling after bone fractures also supports the interaction of MK and PDGF, because MK expression and PDGF accumulation are induced during this process (
      • Ohta S.
      • Muramatsu H.
      • Senda T.
      • Zou K.
      • Iwata H.
      • Muramatsu T.
      ). PTN/HB-GAM promotes the migration of osteoblast-like cells, including UMR106 cells, which provides further evidence (
      • Imai S.
      • Kaksonen M.
      • Raulo E.
      • Kinnunen T.
      • Fages C.
      • Meng X.
      • Lakso M.
      • Rauvala H.
      ).
      MK and PTN/HB-GAM induce the migration of cortical neurons (
      • Maeda N.
      • Noda M.
      ,
      • Maeda N.
      • Ichihara-Tanaka K.
      • Kimura T.
      • Kadomatsu K.
      • Muramatsu T.
      • Noda M.
      ). MK also induces the migration of neutrophils (
      • Takada T.
      • Toriyama K.
      • Muramatsu H.
      • Song X.-J.
      • Torii S.
      • Muramatsu T.
      ). However, only a limited body of information concerning the signaling involved in MK-mediated cell migration is available. We conducted the present study to elucidate the molecular components essential for MK-mediated cell migration, and to test our hypothesis that MK and PDGF could cooperate in cell migration.

      DISCUSSION

      MK has been reported to be induced in areas of a variety of types of tissue injury, such as cerebral and heart infarction, bone fractures, skin burns, and arterial endothelial injury (
      • Yoshida Y.
      • Goto M.
      • Tsutsui J.
      • Ozawa M.
      • Sato E.
      • Osame M.
      • Muramatsu T.
      ,
      • Ohta S.
      • Muramatsu H.
      • Senda T.
      • Zou K.
      • Iwata H.
      • Muramatsu T.
      ,
      • Horiba M.
      • Kadomatsu K.
      • Nakamura E.
      • Muramatsu H.
      • Ikematsu S.
      • Sakuma S.
      • Hayashi K.
      • Yuzawa Y.
      • Matsuo S.
      • Kuzuya M.
      • Kaname T.
      • Hirai M.
      • Saito H.
      • Muramatsu T.
      ,
      • Obama H.
      • Biro S.
      • Tashiro T.
      • Tsutsui J.
      • Ozawa M.
      • Sato E.
      • Osame M.
      • Muramatsu T.
      ,
      • Iwashita N.
      • Muramatsu H.
      • Toriyama K.
      • Torii S.
      • Muramatsu T.
      ). In the case of arterial endothelial injury, we found not only the induction of MK expression in wild-type mice, but also dramatically suppressed neointima formation in MK-deficient mice (
      • Horiba M.
      • Kadomatsu K.
      • Nakamura E.
      • Muramatsu H.
      • Ikematsu S.
      • Sakuma S.
      • Hayashi K.
      • Yuzawa Y.
      • Matsuo S.
      • Kuzuya M.
      • Kaname T.
      • Hirai M.
      • Saito H.
      • Muramatsu T.
      ). The administration of the MK protein to MK-deficient mice caused resumption of neointima formation (
      • Horiba M.
      • Kadomatsu K.
      • Nakamura E.
      • Muramatsu H.
      • Ikematsu S.
      • Sakuma S.
      • Hayashi K.
      • Yuzawa Y.
      • Matsuo S.
      • Kuzuya M.
      • Kaname T.
      • Hirai M.
      • Saito H.
      • Muramatsu T.
      ). Thus, MK seems to be vital for tissue remodeling. The present study revealed another important aspect of the mode of MK action, namely, that it acts synergistically with PDGF in cell migration. PDGF was first purified from platelet α granules and has several important activities, such as mitogenesis and chemotaxis. Because tissue injury is usually accompanied by bleeding and/or cessation of blood flow, an abundance of PDGF can be found in these areas. PDGF expression is also induced during the process of wound healing (
      • Andrew J.G.
      • Hoyland J.A.
      • Freemont A.J.
      • Marsh D.R.
      ). Furthermore, PDGF induces the migration of smooth muscle cells (
      • Ferns G.A.
      • Raines E.W.
      • Sprugel K.H.
      • Motani A.S.
      • Reidy M.A.
      • Ross R.
      ,
      • Rosenkranz S.
      • Kazlauskas A.
      ) and osteoblasts (
      • Tsukamoto T.
      • Matsui T.
      • Fukase M.
      • Fujita T.
      ), and the migration of both is also induced by MK (Ref.
      • Horiba M.
      • Kadomatsu K.
      • Nakamura E.
      • Muramatsu H.
      • Ikematsu S.
      • Sakuma S.
      • Hayashi K.
      • Yuzawa Y.
      • Matsuo S.
      • Kuzuya M.
      • Kaname T.
      • Hirai M.
      • Saito H.
      • Muramatsu T.
      and the present study). Taken together, the synergism between MK and PDGF appears to be pivotal in many in vivo situations.
      Several possibilities should be considered for the mechanism underlying the synergism between MK and PDGF. The present study revealed a difference in the signaling mechanism between MK and PDGF. Heparin inhibited MK-induced cell migration but rather enhanced PDGF-induced cell migration (Figs. 3 A and 9A). MAP kinases were essential for MK-mediated cell migration but not for PDGF-induced cell migration (Figs. 5 and 9). Orthovanadate inhibited MK-induced cell migration but not PDGF-induced cell migration (Fig. 4 C and data not shown). Because distinct signaling molecules are used for cell migration, depending on the ligand (
      • Cospedal R.
      • Abedi H.
      • Zachary I.
      ,
      • Imai Y.
      • Clemmons D.R.
      ), the synergism between MK and PDGF might be attributed to the integration of distinct signaling pathways. Alternatively, induction of MK receptor(s) by PDGF or vice versa should also be considered, as in the case of the induction of the Interleukin-1 receptor or PDGF receptor by the neuropeptide substance P in their synergism in bone marrow fibroblast proliferation (
      • Rameshwar P.
      • Poddar A.
      • Zhu G.
      • Gascon P.
      ). In addition, a third cell surface molecule, such as integrin β1, might be involved in the synergism, like in the case of the synergism between lysophosphatidic acid and epidermal growth factor or PDGF in cell migration (
      • Sakai T.
      • de la Pena J.M.
      • Mosher D.F.
      ).
      MAP kinases (Erk1 and Erk2) can activate myosin light chain kinase and induce changes in the cytoskeletal structure, leading to cell migration (
      • Nguyen D.H.D.
      • Catling A.D.
      • Webb D.J.
      • Sankovic M.
      • Walker L.A.
      • Somlyo A.V.
      • Weber M.J.
      • Gonias S.L.
      ). In this context, it is noteworthy that MK enhances collagen gel contraction by dermal fibroblasts (
      • Sumi Y.
      • Muramatsu H.
      • Hata K.
      • Ueda M.
      • Muramatsu T.
      ). MK-induced MAP kinase activation appeared to be at least partly regulated by PI3-kinase (Fig.6 B). PI3-kinase functions as an early intermediate in Gβγ-mediated MAP kinase activation (
      • Lopez-Ilasaca M.
      • Crespo P.
      • Pellici P.G.
      • Gutkind J.S.
      • Wetzker R.
      ). Several papers have reported that PI3-kinase acts upstream of MAP kinase, e.g.in insulin signaling in 3T3-L1 adipocytes and PDGF signaling in Swiss 3T3 cells (
      • Suga J.
      • Yoshimasa M.
      • Yamada K.
      • Yamamoto Y.
      • Inoue G.
      • Okamoto M.
      • Hayashi T.
      • Shigemoto M.
      • Kosaki A.
      • Kuzuya H.
      • Nakao K.
      ,
      • Duckworth B.C.
      • Cantley L.C.
      ).
      The present study demonstrated that MK recruited PTPζ and PI3-kinase (Fig. 8 B). Furthermore, MK-induced PI3-kinase activation was inhibited by the Src inhibitor PP1 and protein-tyrosine phosphatase inhibitor orthovanadate (Fig. 8 A). Src activation is sometimes needed for PI3-kinase activation (
      • Wong B.R.
      • Besser D.
      • Kim N.
      • Arron J.R.
      • Volvogodskaia M.
      • Hanafusa H.
      • Choi Y.
      ) and requires dephosphorylation at its C-terminal phosphotyrosine, which can be mediated by PTPα (
      • den Hertog J.
      • Pals C.E.G.M.
      • Peppelenbosch M.P.
      • Tertoolen L.G.J.
      • de Laat S.W.
      • Kruijer W.
      ). Taken together, the present results suggest a possible MK signaling cascade, that is, MK binds and activates PTPζ, which then activates Src and PI3-kinase and further activates MAP kinases. However, details of the precise mechanism underlying the interaction between these molecules remain to be elucidated, and other unidentified important molecules may be involved in MK signaling.
      With regard to the sugar structure essential for the binding, the MK and heparin interaction needs all the three sulfate groups in the heparin disaccharide unit (2-O-, N-, and 6-O-sulfation) (
      • Kaneda N.
      • Talukdar A.H.
      • Ishihara M.
      • Hara S.
      • Yoshida K.
      • Muramatsu T.
      ). Dextran sulfate, which has 1.5 sulfate residues per sugar residue, strongly inhibits MK-sulfatide binding (
      • Kurosawa N.
      • Kadomatsu K.
      • Ikematsu S.
      • Sakuma S.
      • Kimura T.
      • Muramatsu T.
      ). In the case of MK binding to PG-M/versican, a matrix chondroitin sulfate proteoglycan, disulfated disaccharides were identified (
      • Zou K.
      • Muramatsu H.
      • Ikematsu S.
      • Sakuma S.
      • Salama R.H.M.
      • Shinomura T.
      • Kimata K.
      • Muramatsu T.
      ). Furthermore, chondroitin sulfate E specifically inhibits MK-dependent neuronal cell adhesion (
      • Ueoka C.
      • Kaneda N.
      • Okazaki I.
      • Nadanaka S.
      • Muramatsu T.
      • Suganuma K.
      ). PTPζ harbors chondroitin sulfate chain, which is important in MK-induced migration of neurons (
      • Maeda N.
      • Ichihara-Tanaka K.
      • Kimura T.
      • Kadomatsu K.
      • Muramatsu T.
      • Noda M.
      ). The present study revealed that the chondroitin sulfate chain in PTPζ is also important in migration of osteoblast-like cells. Differential susceptibility of the migratory activity to chondroitinases with different specificities gave further insights into the nature of chondroitin sulfate chain in PTPζ. Digestion with chondroitinase B abolished MK-dependent migratory activity, whereas chondroitinase AC II did not. The former enzyme acts on chondroitin sulfate chain with thel-iduronic acid residue, namely dermatan sulfate, whereas the latter does not. Thus, it is concluded that chondroitin sulfate, which is important in MK-signaling in PTPζ, has a dermatan sulfate domain. The finding that the MK-induced migration is inhibited by dermatan sulfate is consistent with the view. The MK activity was also inhibited by chondroitin sulfate E, which is an oversulfated chondroitin sulfate with 4,6-disulfo-N-acetylgalactosamine residue. Taken together, most probably the chondroitin sulfate chain in PTPζ, to which MK binds, has an oversulfated structure in a dermatan sulfate domain. Indeed, E-type structure with a dermatan sulfate domain was found in PG-M/versican, which was isolated from mouse embryos and has MK binding activity (
      • Zou K.
      • Muramatsu H.
      • Ikematsu S.
      • Sakuma S.
      • Salama R.H.M.
      • Shinomura T.
      • Kimata K.
      • Muramatsu T.
      ).
      The characteristics of MK-induced migration of UMR106 cells are very similar to those of MK- and PTN/HB-GAM-induced neuronal migration in that PTPζ is involved in haptotactic migration (
      • Maeda N.
      • Noda M.
      ,
      • Maeda N.
      • Ichihara-Tanaka K.
      • Kimura T.
      • Kadomatsu K.
      • Muramatsu T.
      • Noda M.
      ). In this context, the effect of anti-PTPζ antibodies on MK-mediated cell migration was unexpected. These antibodies effectively inhibited PTN/HB-GAM-mediated neuronal migration in the previous study, probably because of competitive inhibition for the PTN/HB-GAM-binding sites of cell surface PTPζ by the antibodies (
      • Maeda N.
      • Ichihara-Tanaka K.
      • Kimura T.
      • Kadomatsu K.
      • Muramatsu T.
      • Noda M.
      ). But in the present study, the antibodies rather enhanced MK-mediated osteoblast-like cell migration. One possible interpretation of this is that PTPζ on UMR106 cells may physically associate with another unidentified component necessary for signal transduction and thus can be readily activated by the oligomerization or conformational change induced by a specific antibody. On nerve cells, PTPζ might need MK to associate with such a component. Supporting our data, Revest et al. (
      • Revest J.-M.
      • Faivre-Sarrailh C.
      • Maeda N.
      • Noda M.
      • Schachner M.
      • Rougon G.
      ) recently reported that cross-linking of PTPζ with antibodies enhances the protein-tyrosine phosphatase activity of C6 astrocytoma cells.
      In this study, we confirmed the involvement of Erk1 and 2 and PI3-kinase in MK-induced cell migration by detecting their active forms or activity induced by MK, in addition to by demonstrating the effects of inhibitors of them. Consistent with our data, Souttou et al. reported that Erk1 and 2 and PI3-kinase are involved in PTN/HB-GAM-mediated cell proliferation (
      • Souttou B.
      • Ahmad S.
      • Riegel A.T.
      • Wellstein A.
      ). In addition, Src, JAK1, and 2 and β-catenin have been reported to be involved in PTN/HB-GAM signaling (
      • Kinnunen T.
      • Kaksonen M.
      • Saarinen J.
      • Kalkkinen N.
      • Peng H.B.
      • Rauvala H.
      ,
      • Ratoviski E.A.
      • Kotzbauer P.T.
      • Milbrandt J.
      • Lowenstein C.J.
      • Burrow C.R.
      ,
      • Meng K.
      • Rodriguez-Pena A.
      • Dimitrov T.
      • Chen W.
      • Yamin M.
      • Noda M.
      • Deuel T.
      ). A study on the possible involvement of these molecules in MK-induced cell migration is underway in our laboratory.

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