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The Osmotic Shock-induced Glucose Transport Pathway in 3T3-L1 Adipocytes Is Mediated by Gab-1 and Requires Gab-1-associated Phosphatidylinositol 3-Kinase Activity for Full Activation*

  • Andrej Janez
    Footnotes
    Affiliations
    Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California 92093
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  • Dorothy Sears Worrall
    Footnotes
    Affiliations
    Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California 92093
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  • Takeshi Imamura
    Affiliations
    Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California 92093
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  • Prem M. Sharma
    Affiliations
    Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California 92093
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  • Jerrold M. Olefsky
    Correspondence
    To whom correspondence should be addressed: Dept. of Medicine (0673), University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0673. Tel.: 858-534-6651; Fax: 858-534-6653; E-mail: [email protected]
    Affiliations
    Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California 92093
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  • Author Footnotes
    * This work was supported in part by NIH Grant DK-33651 and the VA Medical Research Service.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.
    ‡ Supported by a grant from the Slovenian Ministry of Science and Technology.
    § Supported by NIDDK, National Institutes of Health, Individual National Research Service Award Grant DK09595.
Open AccessPublished:September 01, 2000DOI:https://doi.org/10.1016/S0021-9258(19)61455-9
      Osmotic shock treatment of 3T3-L1 adipocytes causes an increase in glucose transport activity and translocation of GLUT4 protein similar to that elicited by insulin treatment. Insulin stimulation of GLUT4 translocation and glucose transport activity was completely inhibited by wortmannin, however, activation by osmotic shock was only partially blocked. Additionally, we have found that the newly identified insulin receptor substrate Gab-1 (Grb2-associated binder-1) is tyrosine-phosphorylated following sorbitol stimulation. Treatment of cells with the tyrosine kinase inhibitor genistein inhibited osmotic shock-stimulated Gab-1 phosphorylation as well as shock-induced glucose transport. Furthermore, pretreatment with the selective Src family kinase inhibitor PP2 completely inhibited the ability of sorbitol treatment to cause tyrosine phosphorylation of Gab-1. We have also shown that microinjection of anti-Gab-1 antibody inhibits osmotic shock-induced GLUT4 translocation. Furthermore, phosphorylated Gab-1 binds and activates phosphatidylinositol 3-kinase (PI3K) in response to osmotic shock. The PI3K activity associated with Gab-1 was 82% of that associated with anti-phosphotyrosine antibodies, indicating that Gab-1 is the major site for PI3K recruitment following osmotic shock stimulation. Although wortmannin only causes a partial block of osmotic shock-stimulated glucose uptake, wortmannin completely abolishes Gab-1 associated PI3K activity. This suggests that other tyrosine kinase-dependent pathways, in addition to the Gab-1-PI3K pathway, contribute to osmotic shock-mediated glucose transport. To date, Gab-1 is the first protein identified as a member of the osmotic shock signal transduction pathway.
      GLUT4
      insulin-responsive glucose transporter isoform
      IRS
      insulin receptor substrate
      Gab-1
      Grb2-associated binder-1
      PI3K
      phosphatidylinositol 3-kinase
      DMEM
      Dulbecco's modified Eagle's medium
      PBS
      phosphate-buffered saline
      SH2
      Src homology 2, GTPγS, guanosine 5′-O-(3-thiotriphosphate)
      TRITC
      tetramethyl-rodamine isothiocyanate
      PAGE
      polyacrylamide gel electrophoresis
      Insulin regulates plasma glucose levels primarily through stimulation of glucose uptake into target tissues and suppression of hepatic glucose production. Glucose transport into adipose and skeletal muscle is predominantly induced by translocation of the insulin responsive glucose transporter isoform GLUT41 from an intracellular pool to the plasma membrane (
      • Holman G.D.
      • Cushman S.W.
      ,
      • James D.E.
      • Piper R.C.
      ,
      • Kandror K.V.
      • Pilch P.F.
      ,
      • Rea S.
      • James D.E.
      ). Although the precise molecular mechanisms and signaling cascades regulating this event have not yet been completely elucidated, recent studies have identified several of the proximal insulin-dependent signaling events. Upon ligand stimulation, the activated insulin receptor tyrosine kinase phosphorylates a variety of intracellular substrates, which are necessary to sort and transmit metabolic or mitogenic signals (
      • Cheatham B.
      • Kahn C.R.
      ,
      • White M.F.
      • Kahn C.R.
      ). Recently, Wong and coworkers (
      • Holgado-Madruga M.
      • Emlet D.R.
      • Moscatello D.K.
      • Godwin A.K.
      • Wong A.J.
      ) cloned a new member of the IRS protein family, called Gab-1 (Grb2-associated binder-1).
      Gab-1 is phosphorylated on tyrosine after stimulation with insulin and several growth factors. It possesses 16 potential phosphotyrosine sites, some of which could serve as binding sites for SH2 domains of the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3K), Grb2, phospholipase C-γ, Nck, and SHP-2. This suggests that Gab-1 serves as a docking protein, like the other IRS proteins. However, in contrast to the IRS proteins, Gab-1 does not possess a phosphotyrosine binding domain, which is believed to be involved in direct binding to the insulin receptor (
      • Rocchi S.
      • Deckert S.T.
      • Murdaca J.
      • Holgado-Madruga M.
      • Wong A.J.
      • Obberghen E.
      ). Little is known about the physiological roles of Gab-1; however, some evidence suggests that it is a part of the signaling pathways leading to cell growth, transformation, and apoptosis (
      • Holgado-Madruga M.
      • Moscatello D.K.
      • Emlet D.R.
      • Dieterich R.
      • Wong A.J.
      ).
      Several studies examining the insulin-stimulated GLUT4 translocation signaling pathway regulating the insulin stimulation of glucose uptake and GLUT4 translocation have demonstrated a role for the activation and/or appropriate targeting of the type I phosphatidylinositol 3-kinase (
      • Shepherd P.R.
      • Siddle K.
      • Nave B.T.
      ,
      • Shepherd P.R.
      • Withers D.J.
      • Siddle K.
      ). Various other stimuli display insulinomimetic properties such as GTPγS or osmotic shock, and can induce translocation of the GLUT4-containing vesicles to the plasma membrane (
      • Elmendorf J.S.
      • Chen D.
      • Pessin J.E.
      ,
      • Haruta T.A.
      • Morris A.J.
      • Vollenweider P.
      • Nelson J.G.
      • Rose D.W.
      • Mueckler M.
      • Olefsky J.M.
      ,
      • Wojtaszewski J.F.
      • Laustsen J.L.
      • Derave W.
      • Richter E.A.
      ,
      • Yeh J.I.
      • Gulve E.A.
      • Rameh L.
      • Birnbaum M.J.
      ), and Chen et al. (
      • Chen D.J.
      • Elmendorf J.S.
      • Olson A.L.
      • Li X.
      • Earp H.S.
      • Pessin J.E.
      ) have shown that osmotic shock stimulates glucose transport activity and translocation of GLUT4 through a novel tyrosine kinase pathway. In the present work we provide evidence that osmotic shock markedly increases Gab1 tyrosine phosphorylation and Gab-1-associated PI3K activity and that these events are necessary for maximal stimulation of glucose transport.

      DISCUSSION

      Over the past several years, significant progress has been made in understanding the molecular mechanisms of insulin action leading to translocation of the GLUT4 glucose transporter from intracellular vesicular storage sites to the plasma membrane in both muscle and adipose cells. However, despite intense study, the signaling pathways mediating this biological effect remain incompletely understood. Several recent studies have observed that osmotic shock is an insulinomimetic agent that increases glucose transport and GLUT4 translocation through a novel tyrosine kinase-dependent pathway whose exact molecular components are, as yet, unidentified (
      • Chen D.J.
      • Elmendorf J.S.
      • Olson A.L.
      • Li X.
      • Earp H.S.
      • Pessin J.E.
      ,
      • Sakaue H.
      • Ogawa W.
      • Takata M.
      • Kuroda S.
      • Kotani K.
      • Matsumoto M.
      • Sakaue M.
      • Nishio S.
      • Ueno H.
      • Kasuga M.
      ). Based on the established knowledge of the insulin signaling pathway, we sought to identify signal transduction events utilized by both insulin and osmotic shock to induce glucose transport and GLUT4 translocation. In our current study, we have identified two proteins that are utilized in osmotic shock signal transduction. First, we find that Gab-1 protein is an important component of the osmotic shock-induced glucose transport pathway. Second, we find that sorbitol treatment activates PI3K through association with tyrosine-phosphorylated Gab-1 protein, which may partially mediate glucose transport stimulation.
      It is now generally accepted that insulin stimulation results in the activation of the insulin receptor tyrosine kinase, leading to tyrosine phosphorylation of the IRS family of intracellular docking proteins and subsequent association, targeting, and activation of PI3K (
      • White M.F.
      • Kahn C.R.
      ,
      • Myers M.G.
      • White M.F.
      ). Several studies have demonstrated that specific PI3K inhibitors (wortmannin and LY-294002) as well as expression of a dominant interfering mutant of the PI3K regulatory subunit (p85) prevent both insulin-stimulated GLUT4 translocation and glucose transport, clearly indicating that PI3K activation is necessary for these functions of insulin (
      • Haruta T.
      • Morris A.J.
      • Rose D.W.
      • Nelson J.G.
      • Mueckler M.
      • Olefsky J.M.
      ,
      • Cheatham B.
      • Vlahos C.J.
      • Cheatham L.
      • Wang L.
      • Blenis J.
      • Kahn C.R.
      ,
      • Okada T.
      • Kawano Y.
      • Sakakibara T.
      • Hazeki O.
      • Ui M.
      ). We and others have previously shown that IRS proteins are not necessary for insulin-stimulated glucose transport (
      • Sharma P.M.
      • Egawa K.
      • Gustafson T.A.
      • Martin J.L.
      • Olefsky J.M.
      ,
      • Morris A.J.
      • Martin S.S.
      • Haruta T.
      • Nelson J.G.
      • Vollenweider P.
      • Gustafson M.
      • Mueckler M.
      • Rose D.W.
      • Olefsky J.M.
      ) and that alternate pathways exist that link the insulin receptor to PI3K. Indeed, we have found that Gαq/11 can be phosphorylated by the insulin receptor leading to activation of PI3K and stimulation of 2-deoxyglucose uptake and GLUT4 translocation (
      • Imamura T.
      • Vollenweider P.
      • Egawa K.
      • Clodi M.
      • Ishibashi K.
      • Nakashima N.
      • Ugi S.
      • Adams J.W.
      • Brown J.H.
      • Olefsky J.M.
      ).
      Glucose transport in adipocytes and muscle can also be stimulated by several other agents, in addition to insulin. For example, exercise induces GLUT4 translocation and glucose uptake in skeletal muscle through an insulin-independent pathway. Introduction of nonhydrolyzable GTP analogues, such as GTPγS, into 3T3-L1 adipocytes or treatment with endothelin-1, both stimulate glucose uptake and GLUT4 translocation independent of insulin (
      • Elmendorf J.S.
      • Chen D.
      • Pessin J.E.
      ,
      • Yeh J.I.
      • Gulve E.A.
      • Rameh L.
      • Birnbaum M.J.
      ,
      • Chen D.J.
      • Elmendorf J.S.
      • Olson A.L.
      • Li X.
      • Earp H.S.
      • Pessin J.E.
      ,
      • Sakaue H.
      • Ogawa W.
      • Takata M.
      • Kuroda S.
      • Kotani K.
      • Matsumoto M.
      • Sakaue M.
      • Nishio S.
      • Ueno H.
      • Kasuga M.
      ,
      • Wu-Wong J.R.
      • Berg C.B.
      • Wang J.
      • Chiou W.J.
      • Fissel B.
      ). Hyperosmolarity, in particular, elicits potent insulin-like properties on glucose metabolism, and activates glucose transport in adipocytes and skeletal muscle (
      • Chen D.J.
      • Elmendorf J.S.
      • Olson A.L.
      • Li X.
      • Earp H.S.
      • Pessin J.E.
      ,
      • Sakaue H.
      • Ogawa W.
      • Takata M.
      • Kuroda S.
      • Kotani K.
      • Matsumoto M.
      • Sakaue M.
      • Nishio S.
      • Ueno H.
      • Kasuga M.
      ). Unlike insulin, these stimuli do not result in the activation of the insulin receptor kinase, suggesting that they may converge with the insulin signaling pathway at a more distal step. Exercise-induced glucose uptake, however, has been shown to be PI3K-independent (
      • Yeh J.I.
      • Gulve E.A.
      • Rameh L.
      • Birnbaum M.J.
      ). In the present study we observed that pretreatment of 3T3-L1 adipocytes with wortmannin partially inhibits osmotic shock-induced glucose transport, suggesting the involvement of a PI3K-dependent pathway as one component in this event. The dose-response curve for wortmannin inhibition of glucose transport is shifted to the right in shock-treated compared with insulin-treated cells, and the maximal inhibitory effect is only 50% compared with >95% in shock- versus insulin-treated cells, respectively. This indicates that PI3K-dependent and -independent mechanisms play a role in osmotic shock-stimulated glucose transport, whereas, the entire effect of insulin involves PI3K signaling. These data agree with the findings of Chen et al. (
      • Chen D.J.
      • Elmendorf J.S.
      • Olson A.L.
      • Li X.
      • Earp H.S.
      • Pessin J.E.
      ), who also showed a PI3K-independent mechanism for shock stimulation of glucose transport, although these investigators were unable to demonstrate a PI3K-dependent component. The rightward shift in the inhibitory curve for shock-treated cells may indicate that PI3K sensitivity to wortmannin varies depending upon subcellular localization and/or binding specificity for different docking proteins (i.e. IRS-1 versus Gab-1). Alternatively, the inhibition of glucose transport that we observed at the higher doses of wortmannin (>100 nm) may be due to its effect on non-PI3K targets in addition to its effects on PI3K.
      We have observed that osmotic shock stimulation of 3T3-L1 adipocytes induces tyrosine phosphorylation of a new member of the IRS family called Gab-1. It is well established that Gab-1 is tyrosine-phosphorylated after insulin or growth factor stimulation (
      • Holgado-Madruga M.
      • Emlet D.R.
      • Moscatello D.K.
      • Godwin A.K.
      • Wong A.J.
      ,
      • Holgado-Madruga M.
      • Moscatello D.K.
      • Emlet D.R.
      • Dieterich R.
      • Wong A.J.
      ,
      • Nguyen L.
      • Holgado-Madruga M.
      • Maroun C.
      • Fixman E.D.
      • Kamikura D.
      • Fournier T.
      • Charest A.
      • Tremblay M.L.
      • Wong A.J.
      • Park M.
      ). Our results show that tyrosine phosphorylation of Gab-1 induced by osmotic shock is 1.5-fold greater than that stimulated by insulin, and it is completely blocked by pretreatment with the tyrosine kinase inhibitor genistein. It is known that the insulin receptor is the tyrosine kinase that mediates insulin-stimulated Gab-1 tyrosine phosphorylation (
      • Rocchi S.
      • Deckert S.T.
      • Murdaca J.
      • Holgado-Madruga M.
      • Wong A.J.
      • Obberghen E.
      ). The precise tyrosine kinase that mediates osmotic shock-stimulated Gab-1 tyrosine phosphorylation is currently still unknown and remains the subject of ongoing studies. However, because Src family kinases can be activated by a variety of stimuli, we postulated that osmotic shock, in some way, activates an Src kinase, which then serves to phosphorylate Gab-1 in tyrosine residues. Our data with the Src kinase inhibitor PP2 are fully consistent with this formulation, because we found that this inhibitor prevented the effect of sorbitol treatment to cause Gab-1 tyrosine phosphorylation.
      Several lines of evidence indicate that this osmotic shock-induced phosphorylation of Gab-1 is functionally important for subsequent stimulation of glucose transport. For example, it is known that the SH2 domains of the p85 subunit of PI3K recognize the motif pYXXM (
      • Songyang Z.
      • Shoelson S.E.
      • Chaudhuri M.
      • Gish G.
      • Pawson T.
      • Haser W.G.
      • King F.
      • Roberts T.
      • Ratnofsky S.
      • Lechleider R.J.
      ). The platelet-derived growth factor receptor contains a YVPM motif, which strongly binds to and directly activates PI3K, and a Y → F mutation in the receptor abolishes platelet-derived growth factor-stimulated PI3K activation (
      • Kazlauskas A.
      • Cooper J.A.
      ). Holgado-Madruga et al. (
      • Holgado-Madruga M.
      • Moscatello D.K.
      • Emlet D.R.
      • Dieterich R.
      • Wong A.J.
      ) showed that Gab-1 contains three such YVPM sequences, which could mediate the binding and subsequent activation of PI3K. It has also been shown that Gab-1 can act as a docking protein for SH2 domain-containing proteins and can mediate PI3K activation upon stimulation with growth factors and insulin (
      • Rocchi S.
      • Deckert S.T.
      • Murdaca J.
      • Holgado-Madruga M.
      • Wong A.J.
      • Obberghen E.
      ,
      • Holgado-Madruga M.
      • Moscatello D.K.
      • Emlet D.R.
      • Dieterich R.
      • Wong A.J.
      ). In the current studies, we find that osmotic shock also stimulates the association of Gab-1 with the p85 subunit of PI3K with subsequent activation of the enzyme. In concordance with our Gab-1 tyrosine phosphorylation results, we also showed that the extent of Gab-1-associated PI3K activity mediated by osmotic shock was greater than that mediated by insulin. Our results also showed that the Gab-1·PI3K complex represents the great majority (>90%) of the osmotic shock-stimulated PI3K activity, whereas Gab-1-associated PI3K accounts for only a minor component of the insulin-stimulated PI3K activity. Treatment of cells with the tyrosine kinase inhibitor, genestin, inhibited shock-stimulated Gab-1 tyrosine phosphorylation, as well as stimulation of glucose transport, consistent with the possibility that these two events are related. To further test this conclusion, we microinjected 3T3-L1 cells with an anti-Gab-1 antibody followed by osmotic shock treatment and measurement of GLUT4 translocation. We found that injection of the Gab-1 antibody had no effect on insulin-stimulated GLUT4 translocation but inhibited osmotic shock-mediated GLUT4 translocation by ∼60%. These results strongly argue that Gab-1 is functionally important for shock-stimulated glucose transport.
      We have previously reported that activation of PI3K is necessary and sufficient to stimulate actin rearrangement, indicating that PI3K may initiate the only signaling cascade required for insulin to induce cytoskeletal restructuring (
      • Martin S.S.
      • Haruta T.
      • Morris A.J.
      • Klippel A.
      • Williams L.T.
      • Olefsky J.M.
      ,
      • Martin S.S.
      • Rose D.W.
      • Saltiel A.R.
      • Klippel A.
      • Williams L.T.
      • Olefsky J.M.
      ,
      • Vollenweider P.
      • Martin S.S.
      • Haruta T.
      • Moriss A.J.
      • Nelson J.G.
      • Cormont M.
      • Brustel Y.
      • Rose D.W.
      • Olefsky J.M.
      ). Data from our present study further demonstrate the involvement of PI3K activity in osmotic shock-mediated membrane ruffling in 3T3-L1 adipocytes. We show that sorbitol stimulation is also capable of inducing membrane ruffling but only up to 50% of the insulin effect. This response is partially blocked by pretreatment with wortmannin.
      The studies described above clearly demonstrate the necessity for Gab-1 in the signaling pathway leading to osmotic shock-stimulated glucose transport and show that this pathway requires PI3K for full activation. Our experiments indicate that PI3K activation occurs in response to osmotic shock, predominantly in association with Gab-1, and partially contributes to both the stimulation of glucose transport and actin rearrangement. It is clear that additional signaling molecules are utilized to elicit osmotic shock-stimulated glucose uptake and actin rearrangement, because these effects are only partially blocked by wortmannin. To date, Gab-1 is the first protein identified as a member of the osmotic shock signal transduction pathway.

      Acknowledgments

      We thank Donna Reichart for maintaining the 3T3-L1 adipocytes.

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