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GTPases and Phosphatidylinositol 3-Kinase Are Critical for Insulin-like Growth Factor-I-mediated Schwann Cell Motility*

  • Hsin-Lin Cheng
    Affiliations
    Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109
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  • Matthew L. Steinway
    Affiliations
    Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109
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  • James W. Russell
    Affiliations
    Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109
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  • Eva L. Feldman
    Correspondence
    To whom correspondence should be addressed: Dept. of Neurology, University of Michigan, 200 Zina Pitcher Place, 4414 Kresge III, Ann Arbor, MI 48109-0588. Tel.: 734-763-7274; Fax: 734-763-7275; E-mail: [email protected]
    Affiliations
    Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109
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  • Author Footnotes
    * This work was supported by National Institutes of Health Grants NS01938 (to J. W. R.), NS36778, and NS38849, grants from the Juvenile Diabetes Foundation Center of Excellence for the Study of the Complications of Diabetes, the American Diabetes Association (to E. L. F.), and the Program for Understanding Neurological Diseases.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Open AccessPublished:September 01, 2000DOI:https://doi.org/10.1016/S0021-9258(19)61497-3
      Previously, we reported insulin-like growth factor-I (IGF-I) promotes motility and focal adhesion kinase (FAK) activation in neuronal cells. In the current study, we examined the role of IGF-I in Schwann cell (SC) motility. IGF-I increases SC process extension and motility. In parallel, IGF-I activates IGF-I receptor, insulin receptor substrate-1 (IRS-1), phosphatidylinositol 3 (PI-3)-kinase, and FAK. LY294002, a PI-3 kinase inhibitor, blocks IGF-I-induced motility and FAK phosphorylation. The Rho family of GTPases is important in the regulation of the cytoskeleton. Overexpression of constitutively active Leu-61 Cdc42 and Val-12 Rac1 enhances SC motility which is unaffected by LY294002. In parallel, stable transfection of SC with dominant negative Asn-17 Rac1 blocks IGF-I-mediated SC motility and FAK phosphorylation, implying Rac is an upstream regulator of FAK. Collectively our results suggest that IGF-I regulates SC motility by reorganization of the actin cytoskeleton via the downstream activation of a PI-3 kinase, small GTPase, and FAK pathway.
      IGF-I
      insulin-like growth factor-I
      FAK
      focal adhesion kinase
      SC
      Schwann cells
      IRS-1
      insulin receptor substrate-1
      PI-3
      phosphatidylinositol 3-kinase
      IGF-IR
      IGF-I receptor
      MAP
      mitogen-activated protein
      DRG
      dorsal root ganglion
      DMEM
      Dulbecco's modified essential media
      DiI
      dioctadecylindocarbocyanine
      GTPγS
      guanosine 5′-3-O-(thio)triphosphate
      SF/HGF
      scatter factor/hepatocyte growth factor
      Insulin-like growth factor-I (IGF-I)1 is a polypeptide growth factor essential for normal nervous system development (
      • Hepler J.E.
      • Lund P.K.
      ,
      • Bondy C.A.
      • Lee W.-H.
      ,
      • LeRoith D.
      • Werner H.
      • Faria T.N.
      • Kato H.
      • Adamo M.
      • Roberts Jr., C.T.
      ).In vitro, IGF-I is a potent mitogenic and survival factor for neurons (
      • Martin D.M.
      • Feldman E.L.
      ,
      • Matthews C.C.
      • Feldman E.L.
      ) and glia (
      • Cheng H.-L.
      • Randolph A.
      • Yee D.
      • Delafontaine P.
      • Tennekoon G.
      • Feldman E.L.
      ,
      • Dong Z.
      • Brennan A.
      • Liu N.
      • Yarden Y.
      • Lefkowitz G.
      • Mirsky R.
      • Jessen K.R.
      ). Our recent studies show IGF-I also promotes changes in the actin cytoskeleton frequently associated with cellular motility (
      • Leventhal P.S.
      • Shelden E.A.
      • Kim B.
      • Feldman E.L.
      ,
      • Leventhal P.S.
      • Feldman E.L.
      ). IGF-I treatment of SH-SY5Y human neuroblastoma cells results in redistribution of the actin cytoskeleton with the formation of rapidly moving membrane ruffles. Ruffling is followed by protrusion of lamellipodia that adhere to specific extracellular matrix molecules and activate cell surface integrins (
      • Leventhal P.S.
      • Feldman E.L.
      ,
      • Huttenlocher A.
      • Sandborg R.R.
      • Horwitz A.F.
      ). Integrin-mediated adhesion activates focal adhesion proteins that form adhesion sites prior to neuroblastoma movement (
      • Leventhal P.S.
      • Feldman E.L.
      ,
      • Huttenlocher A.
      • Sandborg R.R.
      • Horwitz A.F.
      ).
      Focal adhesion kinase (FAK) is a key focal adhesion protein present in focal adhesion sites. Focal adhesion sites are aggregations of protein complexes consisting of activated FAK that in turn recruits other proteins, including paxillin, p130Cas, vinculin, and talin. These protein complexes anchor the actin cytoskeleton and provide structural integrity to cells (
      • Schlaepfer D.D.
      • Hunter T.
      ). Phosphorylation of focal adhesion proteins is important for turnover of focal adhesion sites and allows reorganization of the actin cytoskeleton and cellular movement (
      • Casamassima A.
      • Rozengurt E.
      ). Similar to integrin-ligand binding, IGF-I also phosphorylates and activates focal adhesion proteins, including FAK and paxillin (
      • Leventhal P.S.
      • Shelden E.A.
      • Kim B.
      • Feldman E.L.
      ). IGF-I activation of FAK is dependent on an intact cytoskeleton, suggesting cross-talk between integrins and IGF-I downstream signaling cascades in cellular motility.
      Another family of proteins, the Rho family of small GTPases, are instrumental in regulating the cytoskeleton (
      • Hall A.
      ,
      • Hall A.
      ). Included in this family are Rho, Cdc42, and Rac. In fibroblasts, microinjection of wild-type Rac, a constitutively active mutant Rac, or GTPγS-bound (activated) Rac causes growth factor-independent actin polymerization and concomitant membrane ruffling and lamellipodial advance (
      • Ridley A.J.
      • Paterson H.F.
      • Johnston C.L.
      • Diekmann D.
      • Hall A.
      ,
      • Nobes C.D.
      • Hall A.
      ,
      • Kotani K.
      • Hara K.
      • Yoneawa K.
      • Kasuga K.
      ,
      • Nishiyama T.
      • Sasaki T.
      • Takaishi K.
      • Kato M.
      • Yaku H.
      • Araki K.
      • Matsuura Y.
      • Takai Y.
      ). In these same cells, microinjection of a dominant negative form of Rac blocks the extension of lamellipodia and membrane ruffling in response to insulin (
      • Ridley A.J.
      • Paterson H.F.
      • Johnston C.L.
      • Diekmann D.
      • Hall A.
      ). In mammary epithelial cells, Cdc42 and Rac1 participate in integrin-mediated actin reorganization and cell motility (
      • Keely P.J.
      • Westwick J.K.
      • Whitehead I.P.
      • Der C.J.
      • Parise L.V.
      ), whereas small GTPases are required in platelet-derived growth factor-induced changes in morphology and motility of fibroblasts (
      • Hooshmand-Rad R.
      • Claesson-Welsh L.
      • Wennström S.
      • Yokote K.
      • Siegbahn A.
      • Heldin C.-H.
      ).
      Little is known about the interactions between IGF-I, the small GTPases, and the focal adhesion proteins, including FAK, and how these interacting factors function to promote the motility and/or migration of cells in the nervous system during normal development and in response to injury (
      • Jessen K.R.
      • Mirsky R.
      ). In the current study, we explored the downstream signaling pathways of IGF-I-mediated cellular motility and the roles of FAK and the small Rho family GTPases, Rac and Cdc 42 in Schwann cell (SC) motility. These cells migrate and attach to axons as the nervous system develops and in response to injury in the adult (
      • Jessen K.R.
      • Mirsky R.
      ,
      • Barker F, G.
      • Israel M.A.
      ).
      In the current study, IGF-I enhances motility of cultured rat SC. Cytochalasin D blocks IGF-I-induced SC motility, suggesting this process is dependent on rearrangement of the actin cytoskeleton. In SC, IGF-I activates mitogen-activated protein kinase and phosphatidylinositol 3 (PI-3)-kinase pathways, and FAK. An inhibitor of PI-3 kinase (LY294002) blocks the effects of IGF-I on cell motility and FAK phosphorylation, implying PI-3 kinase signaling is important for IGF-I-induced motility. To test the role of the small GTPases in IGF-I-mediated changes in motility, we used constitutively active or dominant negative mutants of Cdc42 and Rac. Cdc42 and Rac mediate IGF-I-induced cell motility, and both proteins are activated upstream of FAK. We then cocultured SC with dorsal root ganglion (DRG) neurons as an in vitro model of developing peripheral nerves. In this model, IGF-I enhanced attachment of SC to axons. Our results suggest that small GTPases and FAK may serve as linkers between growth factor activation and SC motility which, in turn, promotes the attachment of SC to axons in the nervous system.

      DISCUSSION

      IGF-I is a motility factor for melanoma cells (
      • Stracke M.L.
      • Engel J.D.
      • Wilson L.W.
      • Rechler M.M.
      • Liotta L.A.
      • Schiffmann E.
      ,
      • Stracke M.L.
      • Kohn E.C.
      • Aznavoorian S.A.
      • Wilson L.L.
      • Salomon D.
      • Krutzsch H.C.
      • Liotta L.A.
      • Schiffmann E.
      ), ectoplacental cone cells (
      • Kanai-Azuma M.
      • Kanai Y.
      • Kurohmaru M.
      • Sakai S.
      • Hayashi Y.
      ), arterial smooth muscle cells (
      • Bornfeldt K.E.
      • Raines E.W.
      • Nakano T.
      • Graves L.M.
      • Krebs E.G.
      • Ross R.
      ), vascular endothelial cells (
      • Nakao-Hayashi J.
      • Ito H.
      • Kanayasu T.
      • Morita I.
      • Murota S.
      ), and corneal epithelial cells (
      • Nishida T.
      • Nakamura M.
      • Ofuji K.
      • Reid T.W.
      • Mannis M.J.
      • Murphy C.J.
      ). Our results suggest IGF-I is also a motility factor for SC. In the current studies, IGF-I enhances SC motility which facilitates the contact of SC with axons, and, as we have previously reported leads to nervous system myelination (
      • Cheng H.-L.
      • Russell J.W.
      • Feldman E.L.
      ). These data support recent reports of IGF-I being a necessary factor for SC survival and nervous system myelination (
      • Jessen K.R.
      • Mirsky R.
      ,
      • Gavrilovic J.
      • Brennan A.
      • Mirsky R.
      • Jessen K.R.
      ,
      • Meier C.
      • Parmantier E.
      • Brennan A.
      • Mirsky R.
      • Jessen K.R.
      ).
      To understand the mechanisms underlying IGF-I-mediated SC motility, we initially examined the effects of IGF-I on SC architecture. Phalloidin staining of actin reveals that IGF-I treatment reorganized the SC actin cytoskeleton leading to SC process extension. These findings are in agreement with our recent reports (
      • Leventhal P.S.
      • Shelden E.A.
      • Kim B.
      • Feldman E.L.
      ,
      • Leventhal P.S.
      • Feldman E.L.
      ) in neuroblastoma cells and those of Abrass and colleagues (
      • Berfield A.K.
      • Spicer D.
      • Abrass C.K.
      ) in kidney mesangial cells. In both cell types, IGF-I treatment results in reorganization of the actin cytoskeleton and membrane ruffling.
      Cytochalasin D treatment blocks the effects of IGF-I on SC motility, suggesting that the rearrangement of the SC actin cytoskeleton after IGF-I treatment is essential to initiate motility. Similar findings are reported in microglial cells (
      • Nolte C.
      • Moller T.
      • Walter T.
      • Kettenmann H.
      ) and macrophages (
      • Allen W.E.
      • Jones G.E.
      • Pollard J.W.
      • Ridley A.J.
      ). In most cell types studied, growth factor-mediated changes in the cytoskeleton are followed by activation of focal adhesion proteins (
      • Leventhal P.S.
      • Feldman E.L.
      ,
      • Kumar C.C.
      ). In our studies, IGF-I reorganization of the SC actin cytoskeleton and subsequent enhancement of motility is temporally associated with activation of the IGF-IR and FAK. Our results support the idea that growth factors that reshape the cytoskeleton also activate focal adhesion proteins allowing cells to crawl over their substrates (
      • Leventhal P.S.
      • Feldman E.L.
      ). We have also reported IGF-I activation of FAK and paxillin occurs after IGF-I-mediated membrane ruffling and extension of lamellipodia in neuroblastoma cells (
      • Leventhal P.S.
      • Shelden E.A.
      • Kim B.
      • Feldman E.L.
      ) and that cytochalasin D disrupts IGF-I-induced paxillin (
      • Leventhal P.S.
      • Shelden E.A.
      • Kim B.
      • Feldman E.L.
      ) and FAK (
      • Kim B.
      • Feldman E.L.
      ) phosphorylation. These data strongly suggest that IGF-I treatment produces cytoskeletal remodeling and activation of focal adhesion proteins which leads to cell motility (
      • Leventhal P.S.
      • Shelden E.A.
      • Kim B.
      • Feldman E.L.
      ,
      • Kim B.
      • Feldman E.L.
      ).
      Our results with IGF-I in SC are in agreement with recent reports in non-nervous system cells using other growth factors. Scatter factor/hepatocyte growth factor (SF/HGF) increases motility and induces FAK phosphorylation in fibroblasts (
      • Matsumoto K.
      • Nakamura T.
      • Kramer R.H.
      ). Platelet-derived growth factor enhances the motility of vascular smooth muscle cells and fibroblasts in a dose-dependent manner that correlates with phosphorylation of FAK and paxillin (
      • Abedi H.
      • Dawes K.E.
      • Zachary I.
      ). Finally, cells from FAK-deficient mice are less mobile than corresponding cells from control mice (
      • Ilic D.
      • Kanazawa S.
      • Furuta Y.
      • Yamamoto T.
      • Aizawa S.
      ,
      • Ilic D.
      • Furuta Y.
      • Kanazawa S.
      • Takeda N.
      • Sobue K.
      • Nakatsuji N.
      • Nomura S.
      • Fujimoto J.
      • Okada M.
      • Yamamoto T.
      • Aizawa S.
      ).
      Our current study suggests PI-3 kinase pathways, instead of MAP kinase pathways, mediate IGF-I-induced motility. In support of our findings, Wang and colleagues (
      • Wang M.H.
      • Montero-Julian F.A.
      • Dauny I.
      • Leonard E.J.
      ) reported PI-3 kinase activation is required for migration of epithelial cells after treatment with human macrophage-stimulating protein. PI-3 kinase also mediates SF/HGF-induced motility in kidney cells (
      • Royal I.
      • Fournier T.M.
      • Park M.
      ) and epidermal growth factor receptor-regulated motility in bladder cancer cells (
      • Theodorescu D.
      • Laderoute K.R.
      • Gulding K.M.
      ). Finally, similar to our findings, Adam and colleagues (
      • Adam L.
      • Vadlamudi R.
      • Kondapaka S.B.
      • Chernoff J.
      • Mendelsohn J.
      • Kumar R.
      ) reported PI-3 kinase is required for heregulin-induced cytoskeletal reorganization. Collectively, our results and those of others (
      • Wang M.H.
      • Montero-Julian F.A.
      • Dauny I.
      • Leonard E.J.
      ,
      • Royal I.
      • Fournier T.M.
      • Park M.
      ,
      • Theodorescu D.
      • Laderoute K.R.
      • Gulding K.M.
      ,
      • Adam L.
      • Vadlamudi R.
      • Kondapaka S.B.
      • Chernoff J.
      • Mendelsohn J.
      • Kumar R.
      ) suggest activation of PI-3 kinase is the universal pathway for cell motility induced by a variety of growth factors.
      The family of Rho GTPases are important in regulating the actin cytoskeleton (
      • Schmidt A.
      • Hall M.N.
      ). Our data suggest Cdc42 and Rac mediate the effects of IGF-I on SC motility. In support of our findings, Ridley and colleagues (
      • Ridley A.J.
      • Comoglio P.M.
      • Hall A.
      ) report that SF/HGF mediates changes in the cytoskeleton and subsequent motility in Madin-Darby canine kidney cells via activation of Ras and Rac. In addition, Altun-Gultekin and colleagues (
      • Altun-Gultekin Z.F.
      • Wagner J.A.
      ) find that Rac mediates nerve growth factor and phorbol 12-myristate 13-acetate-induced lamellipodia formation and cell migration in PC12 cells. By using constitutively active mutants (Leu-61 Cdc42 and Val-12 Rac1), we find both Cdc42 and Rac are downstream of PI-3 kinase. These results agree with data from Hoosehmand-Rad and colleagues (
      • Hooshmand-Rad R.
      • Claesson-Welsh L.
      • Wennström S.
      • Yokote K.
      • Siegbahn A.
      • Heldin C.-H.
      ); in their studies platelet-derived growth factor mediates rearrangement of the actin cytoskeleton and motility in porcine aortic endothelial cells via activation of PI-3 kinase and more downstream activation of Rac. Indeed, Tolias and colleagues (
      • Tolias K.F.
      • Cantley L.C.
      • Carpenter C.L.
      ) report there is direct binding of PI-3 kinase with both Rac1 and Cdc42 using coimmunoprecipitation. Although Cdc42 and Rac both associate with PI-3 kinase, Nobes and Hall (
      • Nobes C.D.
      • Hall A.
      ) speculate Cdc42 is upstream of Rac in actin cytoskeletal reorganization. Asn-17 Cdc42 blocks both bradykinin-induced filapodial extension and membrane ruffling; however, Asn-17 Rac inhibits only membrane ruffling. Our data would suggest both Cdc42 and Rac1 play similar roles in IGF-I-induced motility.
      In our studies, stable transfection of SC with dominant negative Asn-17 Rac1 blocks IGF-I-mediated FAK phosphorylation, implying Rac is an upstream regulator of FAK. Several proteins, including FAK, may interact with Rac to mediate changes in the actin cytoskeleton (
      • Schmidt A.
      • Hall M.N.
      ). Tapia and colleagues (
      • Tapia J.A.
      • Camello C.
      • Jensen R.T.
      • Garcia L.J.
      ) find that inhibition of Rho activity in rat pancreatic acini blocks epidermal growth factor-induced FAK phosphorylation and integrity of the actin cytoskeleton. We failed to coimmunoprecipitate FAK with Rac (data not shown), suggesting in SC there are intermediate molecules between Rac and FAK. In support of this idea, Taylor and colleagues (
      • Taylor J.M.
      • Hildebrand J.D.
      • Mack C.P.
      • Cox M.E.
      • Parsons J.T.
      ) recently discovered a GTPase-activating protein (Graf) contains an SH3 domain that associates with FAK, providing a potential link between Rac and FAK.
      In addition to playing important roles in growth factor receptor signaling of cellular motility, PI-3 kinase, small GTPases, and FAK are also essential for integrin-mediated cell motility. Like growth factor receptor activation, integrin ligand binding by extracellular matrix proteins stimulates cytoskeletal rearrangement and cell motility (
      • Schmidt A.
      • Hall M.N.
      ). Integrin activation leads to focal adhesion complex formation that involves activation of Cdc42, Rac, and FAK (
      • Leventhal P.S.
      • Feldman E.L.
      ,
      • Kumar C.C.
      ,
      • Leventhal P.S.
      • Feldman E.L.
      ). Thus, both IGF-IR and integrin-signaling cascades activate PI-3 kinase, small GTPases, and FAK, suggesting bidirectional communication between IGF-IR and integrin signaling (Fig. 9). In support of this idea, occupancy of αVβ3integrin inhibits IGF-I signaling in vascular smooth muscle cells (
      • Zheng B.
      • Clemmons D.R.
      ), and in breast cancer cells integrin activation is necessary to complete IGF-I-induced cell migration (
      • Doerr M.E.
      • Jones J.I.
      ). We are currently examining the interactions between integrin and IGF-I signaling in SC and speculate that cross-talk between the downstream signals of integrin ligand binding and IGF-IR activation are essential for not only cell motility but also cell survival in the nervous system.
      Figure thumbnail gr9
      Figure 9Signaling pathways mediate IGF-I induction of Schwann cell motility. As demonstrated in the current study, PI-3 kinase, small GTPases, and FAK are involved in IGF-I-induced SC motility. IGF-I binding induces IGF-IR tyrosine kinase activity which activates PI-3 kinase via association with IRS. PI-3 kinase acts as an upstream factor for Cdc42 and Rac. Active GTPases then induce FAK phosphorylation and downstream focal adhesion proteins (paxillin and p130Cas) which dissociate focal adhesions and enhance cell motility.

      Acknowledgments

      We thank Dr. Cunming Duan and Dr. Xiping Xin for technical assistance and Judy Boldt for secretarial assistance.

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