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Extracellular Zinc Activates p70 S6 Kinase through the Phosphatidylinositol 3-Kinase Signaling Pathway*

  • Sunhong Kim
    Affiliations
    From the Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 373-1 Kusong-Dong, Yusong, Taejon 305-701, Republic of Korea
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  • Youngsun Jung
    Affiliations
    From the Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 373-1 Kusong-Dong, Yusong, Taejon 305-701, Republic of Korea
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  • Dohoon Kim
    Affiliations
    From the Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 373-1 Kusong-Dong, Yusong, Taejon 305-701, Republic of Korea
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  • Hyongjong Koh
    Affiliations
    From the Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 373-1 Kusong-Dong, Yusong, Taejon 305-701, Republic of Korea
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  • Jongkyeong Chung
    Correspondence
    Supported by the Korea Advanced Institute of Science and Technology Brain Korea 21 program. To whom correspondence should be addressed. Tel.: 82-42-869-2620; Fax: 82-42-869-2610; E-mail: [email protected] mail.kaist.ac.kr.
    Affiliations
    From the Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 373-1 Kusong-Dong, Yusong, Taejon 305-701, Republic of Korea
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  • Author Footnotes
    * This work was supported by Molecular Medicine Program from Ministry of Science and Technology and a grant from IRC-SRC Program.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:August 25, 2000DOI:https://doi.org/10.1074/jbc.M001975200
      We have studied a possible role of extracellular zinc ion in the activation of p70S6k, which plays an important role in the progression of cells from the G1 to S phase of the cell cycle. Treatment of Swiss 3T3 cells with zinc sulfate led to the activation and phosphorylation of p70S6k in a dose-dependent manner. The activation of p70S6k by zinc treatment was biphasic, the early phase being at 30 min followed by the late phase at 120 min. The zinc-induced activation of p70S6k was partially inhibited by down-regulation of phorbol 12-myristate 13-acetate-responsive protein kinase C (PKC) by chronic treatment with phorbol 12-myristate 13-acetate, but this was not significant. Moreover, Go6976, a specific calcium-dependent PKC inhibitor, did not significantly inhibit the activation of p70S6k by zinc. These results demonstrate that the zinc-induced activation of p70S6k is not related to PKC. Also, extracellular calcium was not involved in the activation of p70S6k by zinc. Further characterization of the zinc-induced activation of p70S6k using specific inhibitors of the p70S6k signaling pathway, namely rapamycin, wortmannin, and LY294002, showed that zinc acted upstream of mTOR/FRAP/RAFT and phosphatidylinositol 3-kinase (PI3K), because these inhibitors caused the inhibition of zinc-induced p70S6k activity. In addition, Akt, the upstream component of p70S6k, was activated by zinc in a biphasic manner, as was p70S6k. Moreover, dominant interfering alleles of Akt and PDK1 blocked the zinc-induced activation of p70S6k, whereas the lipid kinase activity of PI3K was potently activated by zinc. Taken together, our data suggest that zinc activates p70S6k through the PI3K signaling pathway.
      p70S6k
      p70 S6 kinase
      PI3K
      phosphatidylinositol 3-kinase
      EGF
      epidermal growth factor
      PMA
      phorbol 12-myristate 13-acetate
      PDK1
      phosphoinositide-dependent kinase 1
      HA
      hemagglutinin
      PKC
      protein kinase C
      p70 S6 kinase (p70S6k)1was originally recognized as the kinase that regulates the multiple phosphorylation of the 40 S ribosomal protein S6 in vivo(
      • Grammer T.C.
      • Cheatham L.
      • Chou M.M.
      • Blenis J.
      ,
      • Proud C.G.
      ,
      • Belham C.
      • Wu S.
      • Avruch J.
      ,
      • Dufner A.
      • Thomas G.
      ). Physiological roles of the kinase have been sought using various molecular and pharmacological methods for the past decade. Most worth noting, the inhibition of agonist-induced p70S6k activationin vivo by either microinjecting neutralizing antibodies (
      • Lane H.A.
      • Fernandez A.
      • Lamb N.J.
      • Thomas G.
      ) or by treatment with the immunosuppressant rapamycin to the cell severely impairs the progression of the cell cycle through the G1 phase (
      • Chung J.
      • Kuo C.J.
      • Crabtree G.R.
      • Blenis J.
      ,
      • Kuo C.J.
      • Chung J.
      • Fiorentino D.F.
      • Flanagan W.M.
      • Blenis J.
      • Crabtree G.R.
      ,
      • Price D.J.
      • Grove J.R.
      • Calvo V.
      • Avruch J.
      • Bierer B.E.
      ). This strongly supports that p70S6k plays important roles during cell growth in the G1 to S cell cycle transition. Further emphasizing the importance of p70S6k at a molecular level is that the kinase is involved in the selective translational regulation of a unique family of mRNAs (
      • Jefferies H.B.
      • Fumagalli S.
      • Dennis P.B.
      • Reinhard C.
      • Pearson R.B.
      • Thomas G.
      ), presumably by mediating the multiple phosphorylation of 40 S ribosomal protein S6. These mRNAs encode for components of the translational apparatus, including ribosomal proteins and translational elongation factors whose increased expression is essential for cell growth and proliferation (
      • Amaldi F.
      • Pierandrei-Amaldi P.
      ).
      Recently, Thomas' group (
      • Montagne J.
      • Stewart M.J.
      • Stocker H.
      • Hafen E.
      • Kozma S.C.
      • Thomas G.
      ) has shown that a mutant fly that has lost the p70S6k ortholog displays delayed growth and reduced cell and body size compared with those of the wild type fly. These genetic studies inDrosophila melanogaster clearly demonstrate that p70S6k and its downstream targets are not only involved in growth at the cellular level but also affect the development and growth of organs and the organism as a whole.
      Although numerous agonists such as growth factors, cytokines, phorbol esters, calcium, inhibitors of protein synthesis, and hormones can activate p70S6k, still little is known about the direct regulators of p70S6k (
      • Grammer T.C.
      • Cheatham L.
      • Chou M.M.
      • Blenis J.
      ,
      • Proud C.G.
      ,
      • Belham C.
      • Wu S.
      • Avruch J.
      ,
      • Dufner A.
      • Thomas G.
      ). Many studies utilizing either point mutational analysis of platelet-derived growth factor receptor (
      • Chung J.
      • Grammer T.C.
      • Lemon K.P.
      • Kazlauskas A.
      • Blenis J.
      ), various PI3K mutants (
      • Weng Q.P.
      • Andrabi K.
      • Klippel A.
      • Kozlowski M.T.
      • Williams L.T.
      • Avruch J.
      ), or specific inhibitors for PI3K such as wortmannin and LY294002 (
      • Chung J.
      • Grammer T.C.
      • Lemon K.P.
      • Kazlauskas A.
      • Blenis J.
      ,
      • Cheatham B.
      • Vlahos C.J.
      • Cheatham L.
      • Wang L.
      • Blenis J.
      • Kahn C.R.
      ) have shown that PI3K is an upstream regulator of p70S6k. In addition, recent progresses in the understanding of the PI3K signaling have led to the discovery of two upstream regulators of p70S6k. The pleckstrin homology domain containing protein kinase phosphoinositide-dependent protein kinase 1 (PDK1) has been identified as the kinase responsible for phosphorylating threonine 229 in the activation loop of p70S6k (
      • Pullen N.
      • Dennis P.B.
      • Andjelkovic M.
      • Dufner A.
      • Kozma S.C.
      • Hemmings B.A.
      • Thomas G.
      ). Interestingly, PDK1 phosphorylates and activates another pleckstrin homology domain containing protein kinase, Akt, as well (
      • Alessi D.R.
      • James S.R.
      • Downes C.P.
      • Holmes A.B.
      • Gaffney P.R.
      • Reese C.B.
      • Cohen P.
      ,
      • Stephens L.
      • Anderson K.
      • Stokoe D.
      • Erdjument-Bromage H.
      • Painter G.F.
      • Holmes A.B.
      • Gaffney P.R.
      • Reese C.B.
      • McCormick F.
      • Tempst P.
      • Coadwell J.
      • Hawkins P.T.
      ). Because p70S6k and Akt share PDK1 as a common upstream regulator, it appears that the PI3K signaling pathway is branched at the level of PDK1 in vivo. However, overexpression of constitutively active or dominantly negative forms of Akt also regulates p70S6k accordingly in vivo (
      • Burgering B.M.
      • Coffer P.J.
      ,
      • Kohn A.D.
      • Summers S.A.
      • Birnbaum M.J.
      • Roth R.A.
      ), suggesting that the PI3K signaling pathway is not a typical kinase cascade as exemplified in the mitogen-activated protein kinase pathways.
      In addition to these complex mechanisms, another signaling molecule is also involved in the regulation of p70S6k. The immunosuppressant rapamycin strongly inhibits p70S6k in vivo, which is a consequence of the inhibition of the activity of mammalian target of rapamycin (mTOR/FRAP/RAFT) (
      • Brown E.J.
      • Albers M.W.
      • Shin T.B.
      • Ichikawa K.
      • Keith C.T.
      • Lane W.S.
      • Schreiber S.L.
      ,
      • Sabatini D.M.
      • Erdjument-Bromage H.
      • Lui M.
      • Tempst P.
      • Snyder S.H.
      ,
      • Sabers C.J.
      • Martin M.M.
      • Brunn G.J.
      • Williams J.M.
      • Dumont F.J.
      • Wiederrecht G.
      • Abraham R.T.
      ). Although there are strong evidences implicating mTOR as an upstream regulator for p70S6k in vivo (
      • Chung J.
      • Kuo C.J.
      • Crabtree G.R.
      • Blenis J.
      ,
      • Kuo C.J.
      • Chung J.
      • Fiorentino D.F.
      • Flanagan W.M.
      • Blenis J.
      • Crabtree G.R.
      ,
      • Price D.J.
      • Grove J.R.
      • Calvo V.
      • Avruch J.
      • Bierer B.E.
      ,
      • Brown E.J.
      • Beal P.A.
      • Keith C.T.
      • Chen J.
      • Shin T.B.
      • Schreiber S.L.
      ), the exact molecular mechanism by which mTOR regulates p70S6k still remains elusive. In conclusion, such complexity in the regulation of p70S6k is likely due to its activation mechanism, which requires multiple hierarchical phosphorylations by several different kinases.
      Zinc is an important trace element in biological systems. It is redox inert and has important roles in modulating the structural and catalytic activities of many cellular proteins. There has been circumstantial evidence suggesting that zinc might be involved in several neurological dysfunctions and other diseases (
      • Choi D.W.
      • Koh J.Y.
      ,
      • Cuajungco M.P.
      • Lees G.J.
      ). For example, zinc interacts with β-amyloid and its precursor protein, which are believed to be involved in the pathogenesis of degenerative processes in the brain, particularly in Alzheimer's disease (
      • Bush A.I.
      • Multhaup G.
      • Moir R.D.
      • Williamson T.G.
      • Small D.H.
      • Rumble B.
      • Pollwein P.
      • Beyreuther K.
      • Masters C.L.
      ). On the other hand, recent experimental evidences support that zinc is involved in cell growth and death in general in vivo (
      • Choi D.W.
      • Koh J.Y.
      ,
      • Cuajungco M.P.
      • Lees G.J.
      ). For example, zinc potentiates the mitogenic signaling of insulin (
      • Kiss Z.
      • Crilly K.S.
      • Tomono M.
      ) and activates extracellular signal-regulated kinase-mitogen-activated protein kinase 1 and 2 (
      • Park J.A.
      • Koh J.Y.
      ). In addition, tyrosine phosphorylations of epidermal growth factor (EGF) receptor are induced by zinc in human epithelial cell lines (
      • Wu W.
      • Graves L.M.
      • Jaspers I.
      • Devlin R.B.
      • Reed W.
      • Samet J.M.
      ). These findings prompted us to examine the effects of zinc on p70S6k and the PI3K signaling pathway.
      Here, we show that zinc potently activates p70S6k in a biphasic manner. This activation is completely inhibitable by rapamycin, wortmannin, and LY294002 and is independent from PKC and extracellular calcium levels. In addition, co-expression of dominantly interfering alleles of Akt and PDK1 strongly blocks the activation of p70S6k by zinc. Furthermore, zinc can activate the lipid kinase activity of PI3K. Thus, we conclude that zinc activates p70S6k via the PI3K signaling pathway in vivo.

      DISCUSSION

      Zinc is present in nearly all body tissues, especially in the thyroid, pancreas, brain, and reproductive organs (
      • Cuajungco M.P.
      • Lees G.J.
      ). This mineral is involved in the body's enzymatic reactions, protein synthesis, and carbohydrate metabolism, etc. In addition, zinc is essential for cell growth and is required for healing and maintaining healthy tissues. It has been understood that these important physiological roles of zinc might stem from the cofactor-like roles of the divalent ion in the cell. However, a recent output of research, mainly focusing on zinc-mediated neurotoxicity, has implied that zinc itself may be directly involved in various cell signalings (
      • Choi D.W.
      • Koh J.Y.
      ). However, no systematic research has been conducted on how zinc is involved in the regulation of cell growth and survival at the molecular level. Here, we first demonstrate the involvement of zinc in the cell signaling activity of p70S6k through the PI3K signaling pathway. Because the PI3K pathway has important roles in regulating cell growth, apoptosis, and development, our present results not only provide a novel mechanism in the regulation of the p70S6k and the PI3K pathway but also instate zinc as a major player in cell signal transduction.
      Several groups have proposed that zinc can enter cells through calcium channels along with calcium (
      • Koh J.Y.
      • Choi D.W.
      ,
      • Weiss J.H.
      • Hartley D.M.
      • Koh J.Y.
      • Choi D.W.
      ), and Kiss and co-workers (
      • Huang J.S.
      • Mukherjee J.J.
      • Chung T.
      • Crilly K.S.
      • Kiss Z.
      ) reported that extracellular calcium-induced stimulation of DNA synthesis and p70S6k activity in NIH 3T3 was dependent on zinc, leading us to first suspect that zinc regulates p70S6k through calcium- and PKC-dependent mechanisms. However, our results clearly showed that an increase in extracellular zinc strongly stimulates p70S6k in a manner that is independent of both PKC and extracellular calcium (Figs. 3 and 4). These interesting effects of zinc on p70S6k are very similar to those seen following growth factor-mediated cell stimulation (
      • Chung J.
      • Chen R.H.
      • Blenis J.
      ).
      A decade ago, Thomas' group (
      • Susa M.
      • Olivier A.R.
      • Fabbro D.
      • Thomas G.
      ) showed that the EGF-stimulated p70S6k activities exhibit biphasic activation kinetics; the early phase of activation appears at 10–15 min, followed by the late phase at between 30–60 min, which is sensitive to PKC down-regulation. Our data demonstrated that zinc also induces p70S6k and Akt in a biphasic manner (Figs. 1 B and 6). The early peak of p70S6k activity appears at 30 min, and the late peak appears at 120 min following zinc stimulation. Interestingly, the p70S6k activities detected during the early peak is partially (about 30%) sensitive to down-regulation of PKC and to a specific PKC inhibitor, but the late peak is completely insensitive to PKC down-regulation (Fig. 3). This interesting pattern of PKC dependence of the zinc-induced p70S6k activity is highly consistent with our previous results from the platelet-derived growth factor-dependent activation of p70S6k (
      • Chung J.
      • Grammer T.C.
      • Lemon K.P.
      • Kazlauskas A.
      • Blenis J.
      ); p70S6k is regulated by the PKC-dependent pathway and the PI3K-dependent pathway in a 3:7 ratio.
      In this paper, we confirmed that zinc stimulates p70S6k activity through the PI3K-dependent pathway using specific inhibitors of PI3K, wortmannin, and LY294002 (Fig. 5) and a dominant interfering allele of Akt and PDK1 (Fig. 7). Moreover, we demonstrated that zinc stimulates the lipid kinase activity of PI3K (Fig. 9). However, the imminent question of how zinc activates PI3K remains. In Fig. 9, we showed that the PI3K activities associated with the anti-phosphotyrosine immunoprecipitates were raised significantly following in vivo zinc stimulation. This result suggests that tyrosine kinases are involved in the activation of the PI3K signaling pathway by zinc. May and Contoreggi (
      • May J.M.
      • Contoreggi C.S.
      ) have found that zinc exerted the insulin-like effects by generating hydrogen peroxide in isolated rat adipocytes. Intracellular reactive oxygen species induces the tyrosine phosphorylation of numerous cytosolic proteins and activation of growth factor receptor tyrosine kinases such as EGF receptor (
      • Wang X.
      • McCullough K.D.
      • Franke T.F.
      • Holbrook N.J.
      ). Furthermore, oxidative stress activates PI3K and causes the accumulation of phosphatidylinositol 3, 4-bisphosphate, which recruits Akt to the plasma membrane and activates it (
      • Van der Kaay J.
      • Beck M.
      • Gray A.
      • Downes C.P.
      ). From these results, we can postulate a model that zinc induces the generation of reactive oxygen species such as hydrogen peroxide in the cell and consequently activates growth factor receptor tyrosine kinases to stimulate the PI3K signaling pathway.
      Alternatively, zinc may activate nonreceptor tyrosine kinases associated with PI3K. For example, a recent study implicated that focal adhesion kinase, a nonreceptor tyrosine kinase, functions as the upstream mediator of PI3K activation in T98 glioblastoma cells (
      • Sonada Y.
      • Watanabe S.
      • Matsumoto Y.
      • Aizu-Yokota E.
      • Kasahara T.
      ). In addition, focal adhesion kinase and Src family tyrosine kinases were tyrosine-phosphorylated and induced to associate with PI3K in response to hydrogen peroxide treatment (
      • Sonada Y.
      • Watanabe S.
      • Matsumoto Y.
      • Aizu-Yokota E.
      • Kasahara T.
      ,
      • Lander H.M.
      • Ogiste J.S.
      • Teng K.K.
      • Novogrodsky A.
      ,
      • Abe J.
      • Takahashi M.
      • Ishida M.
      • Lee J.D.
      • Berk B.C.
      ). Thus, it is possible that these nonreceptor tyrosine kinases may also be involved in the zinc-mediated activation of PI3K.
      Up to now, the molecular mechanisms behind the role of zinc in cell growth and metabolism have been unknown. The present study suggests that zinc exerts its physiological functions through the PI3K pathway. Further studies on how zinc activates PI3K and on the precise mechanisms through which the PI3K/p70S6k signaling pathway acts to modulate the response to zinc, are needed to fully understand this newly discovered role of zinc in the cell.

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