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Granulocyte-Macrophage Colony-stimulating Factor Signals for Increased Glucose Transport via Phosphatidylinositol 3-Kinase- and Hydrogen Peroxide-dependent Mechanisms*

Open AccessPublished:January 21, 2003DOI:https://doi.org/10.1074/jbc.M212541200
      Granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates cellular glucose uptake by decreasing the apparent K m for substrate transport through facilitative glucose transporters on the plasma membrane. Little is known about this signal transduction pathway and the role of the α subunit of the GM-CSF receptor (αGMR) in modulating transporter activity. We examined the function of phosphatidylinositol 3-kinase (PI 3-kinase) in GM-CSF-stimulated glucose uptake and found that PI 3-kinase inhibitors, wortmannin and LY294002, completely blocked the GM-CSF-dependent increase of glucose uptake in Xenopus oocytes expressing the low affinity αGMR and in human cells expressing the high affinity αβGMR complex. We identified a Src homology 3 domain-binding motif in αGMR at residues 358–361 as a potential interaction site for the PI 3-kinase regulatory subunit, p85. Physical evidence for p85 binding to αGMR was obtained by co-immunoprecipitation with antibodies to αGMR and p85, and an αGMR mutant with alteration of the Src homology 3 binding domain lost the ability to bind p85. Experiments with a construct eliminating most of the intracellular portion of αGMR showed a 50% reduction in GM-CSF-stimulated glucose uptake with residual activity blocked by wortmannin. Searching for a proximally generated diffusible factor capable of activating PI 3-kinase, we identified hydrogen peroxide (H2O2), generated by ligand or antibody binding to αGMR, as the initiating factor. Catalase treatment abrogated GM-CSF- or anti-αGMR antibody-stimulated glucose uptake in αGMR-expressing oocytes, and H2O2 activated PI 3-kinase and led to some stimulation of glucose uptake in uninjected oocytes. Human myeloid cell lines and primary explant human lymphocytes expressing high affinity GM-CSF receptors responded to αGMR antibody with increased glucose uptake. These results identify the early events in the stimulation of glucose uptake by GM-CSF as involving local H2O2 generation and requiring PI 3-kinase activation. Our findings also provide a mechanistic explanation for signaling through the isolated α subunit of the GM-CSF receptor.
      GM-CSF
      granulocyte-macrophage colony-stimulating factor
      GMR
      GM-CSF receptor
      PI
      phosphatidylinositol
      SH-3
      Src homology 3
      GLUT
      glucose transporter
      DOG
      2-deoxy-d-glucose
      ROS
      reactive oxygen species
      IL
      interleukin
      Granulocyte-macrophage colony-stimulating factor (GM-CSF)1 is an important cytokine involved in the growth and maturation of hematopoietic cells and in regulating host defense functions (
      • Gasson J.C.
      ). The receptor for GM-CSF is composed of two subunits, α (αGMR) and β (βGMR), and is found on hematopoietic cells, myeloid progenitors, mature granulocytes, and mononuclear phagocytes (
      • McKinstry W.J.
      • Li C.L.
      • Rasko J.E.
      • Nicola N.A.
      • Johnson G.R.
      • Metcalf D.
      ,
      • Hayashida K.
      • Kitamura T.
      • Gorman D.M.
      • Arai K.
      • Yokota T.
      • Miyajima A.
      ). The GM-CSF receptor is also expressed on non-hematopoietic tissues including endothelial cells, oligodendrocytes, placenta, spermatozoa, prostate, and various immortalized cell lines (
      • Bussolino F.
      • Wang J.M.
      • Defilippi P.
      • Turrini F.
      • Sanavio F.
      • Edgell C.J.
      • Aglietta M.
      • Arese P.
      • Mantovani A.
      ,
      • Avalos B.R.
      • Gasson J.C.
      • Hedvat C.
      • Quan S.G.
      • Baldwin G.C.
      • Weisbart R.H.
      • Williams R.E.
      • Golde D.W.
      • DiPersio J.F.
      ,
      • Baldwin G.C.
      • Gasson J.C.
      • Kaufman S.E.
      • Quan S.G.
      • Williams R.E.
      • Avalos B.R.
      • Gazdar A.F.
      • Golde D.W.
      • DiPersio J.F.
      ,
      • Baldwin G.C.
      • Golde D.W.
      • Widhopf G.F.
      • Economou J.
      • Gasson J.C.
      ,
      • Taketazu F.
      • Chiba S.
      • Shibuya K.
      • Kuwaki T.
      • Tsumura H.
      • Miyazono K.
      • Miyagawa K.
      • Takaku F.
      ,
      • Lee S.C.
      • Liu W.
      • Roth P.
      • Dickson D.W.
      • Berman J.W.
      • Brosnan C.F.
      ,
      • Rivas C.I.
      • Vera J.C.
      • Delgado-Lopez F.
      • Heaney M.L.
      • Guaiquil V.H.
      • Zhang R.H.
      • Scher H.I.
      • Concha I.I.
      • Nualart F.
      • Cordon-Cardo C.
      • Golde D.W.
      ,
      • Hirsch T.
      • Eggstein S.
      • Frank S.
      • Farthmann E.H.
      • von Specht B.U.
      ,
      • Zambrano A.
      • Noli C.
      • Rauch M.C.
      • Werner E.
      • Brito M.
      • Amthauer R.
      • Slebe J.C.
      • Vera J.C.
      • Concha I.I.
      ). The isolated αGMR binds GM-CSF with low affinity (K d 2–5 nm) and forms a complex with βGMR to create the high affinity receptor (K d 30 pm). While the GM-CSF, IL-5, and IL-3 receptors share a common β chain (βGMR), the α subunit is unique to each receptor and determines the binding specificity and the distinct responses mediated by each ligand (
      • Scheid M.P.
      • Lauener R.W.
      • Duronio V.
      ,
      • Geijsen N.
      • Koenderman L.
      • Coffer P.J.
      ). The βGMR subunit plays a central role in GM-CSF cell signaling (
      • Miyajima A.
      • Mui A.L.
      • Ogorochi T.
      • Sakamaki K.
      ); however, the α subunit is also required for signaling mediated by the high affinity receptor beyond its role in ligand binding (
      • Polotskaya A.
      • Zhao Y.
      • Lilly M.L.
      • Kraft A.S.
      ,
      • Moon B.G.
      • Yoshida T.
      • Shiiba M.
      • Nakao K.
      • Katsuki M.
      • Takaki S.
      • Takatsu K.
      ). A direct signaling function for an isolated α subunit was recently elucidated by the finding that the α IL-5 receptor interacts with syntenin, inducing IL-5-mediated transcriptional responses (
      • Geijsen N.
      • Uings I.J.
      • Pals C.
      • Armstrong J.
      • McKinnon M.
      • Raaijmakers J.A.
      • Lammers J.W.
      • Koenderman L.
      • Coffer P.J.
      ).
      It has long been known that cytokines like IL-3 and GM-CSF modulate glucose uptake in hematopoietic cells (
      • Whetton A.D.
      • Bazill G.W.
      • Dexter T.M.
      ,
      • Nefesh I.
      • Bauskin A.R.
      • Alkalay I.
      • Golembo M.
      • Ben-Neriah Y.
      ,
      • Dexter T.M.
      • Whetton A.D.
      • Bazill G.W.
      ,
      • Tan A.S.
      • Ahmed N.
      • Berridge M.V.
      ,
      • Berridge M.V.
      • Tan A.S.
      ,
      • McCoy K.D.
      • Ahmed N.
      • Tan A.S.
      • Berridge M.V.
      ). Stimulation of cellular glucose uptake by cytokines is believed to be part of their function as survival factors by enhancing the availability of substrate for energy generation required for cell metabolism (
      • Vander Heiden M.G.
      • Plas D.R.
      • Rathmell J.C.
      • Fox C.J.
      • Harris M.H.
      • Thompson C.B.
      ). Non-hematopoietic cells expressing high affinity GMR and melanoma cells expressing an isolated αGMR also respond to GM-CSF by increasing glucose uptake (
      • Zambrano A.
      • Noli C.
      • Rauch M.C.
      • Werner E.
      • Brito M.
      • Amthauer R.
      • Slebe J.C.
      • Vera J.C.
      • Concha I.I.
      ,
      • Spielholz C.
      • Heaney M.L.
      • Morrison M.E.
      • Houghton A.N.
      • Vera J.C.
      • Golde D.W.
      ). We previously found that Xenopus oocytes expressing only the isolated αGMR respond to GM-CSF with increased glucose uptake (
      • Ding D.X.
      • Rivas C.I.
      • Heaney M.L.
      • Raines M.A.
      • Vera J.C.
      • Golde D.W.
      ). The only physiological signaling role tentatively assigned to the low affinity GM-CSF receptor, independent of the βGMR, is the regulation of glucose uptake (
      • Tan A.S.
      • Ahmed N.
      • Berridge M.V.
      ,
      • Ding D.X.
      • Rivas C.I.
      • Heaney M.L.
      • Raines M.A.
      • Vera J.C.
      • Golde D.W.
      ). The in vivo relevance of GM-CSF in mediating glucose uptake was demonstrated in the development of preimplantation embryos in mice where an isolated αGMR is expressed without βGMR. Signaling through this low affinity receptor is associated with increased glucose uptake and enhanced proliferation and viability of blastomeres (
      • Robertson S.A.
      • Sjoblom C.
      • Jasper M.J.
      • Norman R.J.
      • Seamark R.F.
      ). Studies with bone marrow from βGMR-null mice, however, have suggested that βGMR may be required for GM-CSF signaling for glucose transport in mouse bone marrow cells (
      • Scott C.L.
      • Hughes D.A.
      • Cary D.
      • Nicola N.A.
      • Begley C.G.
      • Robb L.
      ).
      Neoplastic transformation and viral infection increase cellular glucose uptake through augmented facilitative glucose transporter (GLUT) expression on the cell surface (
      • Medina R.A.
      • Owen G.I.
      ,
      • Siegert W.
      • Monch T.
      ,
      • Corkey R.F.
      • Corkey B.E.
      • Gimbrone Jr., M.A.
      ). Similarly insulin and certain growth factors cause increased GLUT translocation to the cell membrane that is dependent on activation of PI 3-kinase and its downstream targets (
      • Ishizuka T.
      • Kajita K.
      • Miura A.
      • Ishizawa M.
      • Kanoh Y.
      • Itaya S.
      • Kimura M.
      • Muto N.
      • Mune T.
      • Morita H.
      • Yasuda K.
      ,
      • Egawa K.
      • Sharma P.M.
      • Nakashima N.
      • Huang Y.
      • Huver E.
      • Boss G.R.
      • Olefsky J.M.
      ). Up-regulation of glucose transport in a cell model for chronic myeloid leukemia is also mediated via activation of PI 3-kinase (
      • Bentley J.
      • Walker I.
      • McIntosh E.
      • Whetton A.D.
      • Owen-Lynch P.J.
      • Baldwin S.A.
      ). The ability of GM-CSF to decrease the apparentK m of GLUT1 without changing theV max suggests that initial signaling from the GMR results in modulation of the intrinsic properties of the transporters (
      • Spielholz C.
      • Heaney M.L.
      • Morrison M.E.
      • Houghton A.N.
      • Vera J.C.
      • Golde D.W.
      ,
      • Ahmed N.
      • Kansara M.
      • Berridge M.V.
      ,
      • Vera J.C.
      • Rivas C.I.
      • Zhang R.H.
      • Golde D.W.
      ). GM-CSF also signals for increased transport of the oxidized form of vitamin C, as dehydroascorbic acid, through GLUT1 by a similar mechanism (
      • Vera J.C.
      • Rivas C.I.
      • Zhang R.H.
      • Golde D.W.
      ). To elucidate this signaling process and the role of the isolated αGMR, we undertook experiments in frog oocytes expressing αGMR and human cells expressing both the αGMR and βGMR subunits. The results reported here point to a central role for PI 3-kinase in signaling for increased glucose uptake and indicate that hydrogen peroxide generated proximally at the receptor is a key initial signaling event.

      DISCUSSION

      Hematopoietic cytokines stimulate the proliferation of precursor cells and promote the survival and function of mature cells. These processes require energy, and cytokines such as IL-3, lL-1, and GM-CSF are known to enhance glucose transport in target cells (
      • Whetton A.D.
      • Bazill G.W.
      • Dexter T.M.
      ,
      • Nefesh I.
      • Bauskin A.R.
      • Alkalay I.
      • Golembo M.
      • Ben-Neriah Y.
      ,
      • Ding D.X.
      • Rivas C.I.
      • Heaney M.L.
      • Raines M.A.
      • Vera J.C.
      • Golde D.W.
      ,
      • Whetton A.D.
      • Bazill G.W.
      • Dexter T.M.
      ,
      • Hamilton J.A.
      • Vairo G.
      • Lingelbach S.R.
      ,
      • Freedman M.H.
      • Grunberger T.
      • Correa P.
      • Axelrad A.A.
      • Dube I.D.
      • Cohen A.
      ). Transport of glucose across the plasma membrane occurs predominantly through facilitative GLUTs, and cellular glucose uptake can be modulated by regulating the number of transporters on the cell surface and/or by altering their transport efficiency (
      • Gould G.W.
      • Holman G.D.
      ,
      • Cushman S.W.
      • Wardzala L.J.
      ,
      • Cushman S.W.
      • Goodyear L.J.
      • Pilch P.F.
      • Ralston E.
      • Galbo H.
      • Ploug T.
      • Kristiansen S.
      • Klip A.
      ,
      • Bird T.A.
      • Davies A.
      • Baldwin S.A.
      • Saklatvala J.
      ). Both GM-CSF and IL-3 enhance the intrinsic efficiency of GLUT1 as reflected by a decrease in the K m without a change in maximum velocity (V max) (
      • Ahmed N.
      • Kansara M.
      • Berridge M.V.
      ,
      • Vera J.C.
      • Rivas C.I.
      • Zhang R.H.
      • Golde D.W.
      ). GM-CSF stimulates glucose transport in Xenopus oocytes expressing the isolated human αGMR, HL-60 neutrophilic cells expressing the αβGMR heterodimer, and certain other cell types responsive to GM-CSF (
      • Zambrano A.
      • Noli C.
      • Rauch M.C.
      • Werner E.
      • Brito M.
      • Amthauer R.
      • Slebe J.C.
      • Vera J.C.
      • Concha I.I.
      ,
      • Spielholz C.
      • Heaney M.L.
      • Morrison M.E.
      • Houghton A.N.
      • Vera J.C.
      • Golde D.W.
      ,
      • Ding D.X.
      • Rivas C.I.
      • Heaney M.L.
      • Raines M.A.
      • Vera J.C.
      • Golde D.W.
      ,
      • Ahmed N.
      • Kansara M.
      • Berridge M.V.
      ). Little is known, however, about how GM-CSF signals for increased glucose uptake, and there is controversy regarding the requirement for βGMR (
      • Scott C.L.
      • Hughes D.A.
      • Cary D.
      • Nicola N.A.
      • Begley C.G.
      • Robb L.
      ). Signaling from the isolated αGMR for glucose uptake in oocytes does not involve activation of the mitogen-activated protein kinase pathway, and GM-CSF stimulation of glucose uptake in HL-60 neutrophilic cells does not appear to involve activation of kinase pathways that are inhibitable by staurosporine (
      • Ding D.X.
      • Rivas C.I.
      • Heaney M.L.
      • Raines M.A.
      • Vera J.C.
      • Golde D.W.
      ). More recently the in vivo relevance of GM-CSF-stimulated glucose uptake through the low affinity αGMR has been described in the development of preimplantation embryos in mice. These embryos express an isolated αGMR, and there is increased glucose uptake and enhanced proliferation and viability of blastomeres in response to GM-CSF (
      • Robertson S.A.
      • Sjoblom C.
      • Jasper M.J.
      • Norman R.J.
      • Seamark R.F.
      ). We investigated the initial signaling events of GM-CSF-stimulated glucose uptake and sought to mechanistically define a role for the isolated αGMR.
      In oocytes, as in mammalian cells, PI 3-kinase activation has been implicated as an important signaling intermediate for insulin-stimulated glucose uptake (
      • Egert S.
      • Nguyen N.
      • Brosius F.C.
      • Schwaiger M.
      ,
      • Gould G.W.
      • Jess T.J.
      • Andrews G.C.
      • Herbst J.J.
      • Plevin R.J.
      • Gibbs E.M.
      ). We hypothesized that PI 3-kinase was involved in the stimulation of glucose uptake by GM-CSF. In oocytes expressing αGMR, GM-CSF-stimulated glucose uptake was inhibited by wortmannin and a structurally distinct inhibitor of PI 3-kinase, LY294002, in a dose-dependent manner. GM-CSF-stimulated glucose uptake in HL-60 cells expressing the high affinity receptor was also blocked by wortmannin. The inhibitor results therefore implicate the involvement of PI 3-kinase in the stimulation of glucose uptake signaled through αGMR and the αβGMR high affinity receptor. We also found clear evidence for a physical interaction between αGMR and p85. In searching for potential domains of αGMR that interact with p85, we examined an SH-3 domain-binding motif, QRLFPPVP, that is conserved among the GM-CSF, IL-3, and IL-5 receptors in the intracellular membrane proximal region (
      • Moon B.G.
      • Yoshida T.
      • Shiiba M.
      • Nakao K.
      • Katsuki M.
      • Takaki S.
      • Takatsu K.
      ,
      • Matsuguchi T.
      • Zhao Y.
      • Lilly M.B.
      • Kraft A.S.
      ). A tyrosine residue toward the carboxyl end of αGMR (amino acid residue 389) is not in the context of a consensus motif used for p85 binding by certain receptors (
      • Thakker G.D.
      • Hajjar D.P.
      • Muller W.A.
      • Rosengart T.K.
      ,
      • Kontos C.D.
      • Stauffer T.P.
      • Yang W.P.
      • York J.D.
      • Huang L.
      • Blanar M.A.
      • Meyer T.
      • Peters K.G.
      ). Mutation of the SH-3 domain-binding site abrogated the interaction of p85 to αGMR as did a mutation deleting most of the cytoplasmic region of the αGMR. Oocytes expressing these mutants showed GM-CSF-stimulated glucose uptake of about 50% of wild type αGMR. This result suggested that interaction of p85 with the SH-3 domain-binding motif, while required for PI 3-kinase binding, was only partly responsible for GM-CSF-induced glucose uptake. The residual activity of the mutants was dependent on PI 3-kinase activation as it was completely blocked by wortmannin.
      In several cell types insulin elicits rapid production of hydrogen peroxide (
      • Mahadev K.
      • Zilbering A.
      • Zhu L.
      • Goldstein B.J.
      ), and one of the subsequent cell responses to the H2O2 production by insulin is increase in glucose uptake (
      • Mahadev K.
      • Wu X.
      • Zilbering A.
      • Zhu L.
      • Lawrence J.T.
      • Goldstein B.J.
      ). Generation of extracellular peroxide has been demonstrated previously in fibroblasts and endothelial cells treated with transforming growth factor-β and ROS-generating systems such as glucose/glucose oxidase or xanthine/xanthine oxidase can increase glucose uptake in 3T3-L1 adipocytes and L6 myotubes (
      • Kozlovsky N.
      • Rudich A.
      • Potashnik R.
      • Bashan N.
      ). Treatment with peroxidase in these cases inhibited the increase in glucose uptake indicating that extracellular H2O2 was connected to stimulation of glucose transport (
      • Kozlovsky N.
      • Rudich A.
      • Potashnik R.
      • Bashan N.
      ). In addition, GM-CSF is known to use ROS for signaling (
      • Carcamo J.M.
      • Borquez-Ojeda O.
      • Golde D.W.
      ,
      • Sattler M.
      • Winkler T.
      • Verma S.
      • Byrne C.H.
      • Shrikhande G.
      • Salgia R.
      • Griffin J.D.
      ), and ROS can act as a second messenger in cellular signaling by modifying the activity of redox-sensitive enzymes including kinases and phosphatases (
      • Finkel T.
      ,
      • Kamata H.
      • Hirata H.
      ,
      • Suzuki Y.J.
      • Forman H.J.
      • Sevanian A.
      ). We found that catalase and PI 3-kinase inhibitors markedly decreased GM-CSF-stimulated glucose uptake in oocytes expressing wild type or truncated αGMR. Hydrogen peroxide also induced PI 3-kinase-dependent glucose uptake in oocytes expressing wild type and to a lesser extent the truncated αGMR. H2O2 had some activity in stimulating glucose uptake in oocytes not expressing αGMR. The experiments in oocytes expressing αGMR yielded results consistent with the thesis that GM-CSF binding to the low affinity receptor generates H2O2, which then stimulates glucose uptake via the activation of PI 3-kinase.
      Lerner and colleagues (
      • Wentworth Jr., P.
      • Jones L.H.
      • Wentworth A.D.
      • Zhu X.
      • Larsen N.A.
      • Wilson I.A.
      • Xu X.
      • Goddard III, W.A.
      • Janda K.D.
      • Eschenmoser A.
      • Lerner R.A.
      ) have provided strong evidence for antigen-antibody interaction leading to generation of H2O2 through catalysis of molecular oxygen and H2O. We found that anti-αGMR antibody stimulated glucose transport in Xenopus oocytes expressing αGMR and also in HL-60 cells, U937, and peripheral blood lymphocytes in a wortmannin-inhibitable manner. Antibody to αGMR induced glucose uptake that was blocked by catalase, suggesting that peroxide production was mediating induction of glucose uptake.
      The role of the α subunit of the GM-CSF receptor in signal transduction through the high affinity receptor has been illuminated by mutational and structural studies (
      • Matsuguchi T.
      • Zhao Y.
      • Lilly M.B.
      • Kraft A.S.
      ,
      • DiPersio J.F.
      • Golde D.W.
      • Gasson J.D.
      ,
      • Lilly M.B.
      • Zemskova M.
      • Frankel A.E.
      • Salo J.
      • Kraft A.S.
      ,
      • Evans C.A.
      • Ariffin S.
      • Pierce A.
      • Whetton A.D.
      ); however, there has been controversy regarding the ability of the isolated αGMR to signal (
      • Scott C.L.
      • Hughes D.A.
      • Cary D.
      • Nicola N.A.
      • Begley C.G.
      • Robb L.
      ). The results reported here define a signaling system for enhanced glucose uptake dependent on H2O2 generation leading to the activation of PI 3-kinase. The most proximal initiation appears to be peroxide generated from ligand or antibody interaction with the extracellular domain of αGMR. Permeation of peroxide leads to PI 3-kinase activation, which is facilitated by an SH-3 domain-binding motif in the cytoplasmic portion of the αGMR. Since most of the intracellular portion of αGMR is not absolutely required for PI 3-kinase activation, we envision that such activation could occur at a proximal cell membrane location. PI 3-kinase initiates well known signaling pathways; however, it is not known how it causes increased transport by reducing K m. Since vitamin C is transported as dehydroascorbic acid through GLUT1 and its uptake is stimulated by GM-CSF (
      • Vera J.C.
      • Rivas C.I.
      • Zhang R.H.
      • Golde D.W.
      ), the GM-CSF-stimulated PI 3-kinase pathways can operate to enhance cellular antioxidant function as well as provide increased metabolic substrate for cellular function.

      Acknowledgments

      We thank Dr. Isabel Perez-Cruz for isolation of lymphocytes from blood and Oriana Bórquez-Ojeda and Alicia Pedraza for technical help.

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