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Glycogen synthase kinase-3 is a negative regulator of extracellular signal-regulated kinase

Oncogene volume 25, pages 43–50 (2006)Cite this article

Abstract

Glycogen-synthase kinase-3 (GSK-3) and extracellular signal-regulated kinase (ERK) are critical downstream signaling proteins for the PI3-kinase/Akt and Ras/Raf/MEK-1 pathway, respectively, and regulate diverse cellular processes including embryonic development, cell differentiation and apoptosis. Here, we show that inhibition of GSK-3 using GSK-3 inhibitors or RNA interference (RNAi) significantly induced the phosphorylation of ERK1/2 in human colon cancer cell lines HT29 and Caco-2. Pretreatment with the PKCδ-selective inhibitor rottlerin or transfection with PKCδ siRNA attenuated the phosphorylation of ERK1/2 induced by the GSK-3 inhibitor SB-216763 and, furthermore, treatment with SB-216763 or transfection with GSK-3α and GSK-3β siRNA increased PKCδ activity, thus identifying a role for PKCδ in the induction of ERK1/2 phosphorylation by GSK-3 inhibition. Treatment with SB-216763 increased expression of cyclooxygenase-2 (COX-2) and IL-8, which are downstream targets of ERK1/2 activation; this induction was abolished by MEK/ERK inhibition, suggesting GSK-3 inhibition induced COX-2 and IL-8 through ERK1/2 activation. The transcriptional induction of COX-2 and IL-8 by GSK-3 inhibition was further demonstrated by the increased COX-2 and IL-8 promoter activity after SB-216763 treatment or transfection with GSK-3α or GSK-3β siRNA. Importantly, our findings identify GSK-3, acting through PKCδ, as a negative regulator of ERK1/2, thus revealing a novel crosstalk mechanism between these critical signaling pathways.

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Abbreviations

GSK-3:

glycogen-synthase kinase-3

COX-2:

cyclooxygenase-2

ERK:

extracellular signal-regulated kinase

LiCl:

lithium chloride

MAPK:

mitogen-activated protein kinase

MBP:

myelin basic protein

References

  • Aikin R, Maysinger D, Rosenberg L . (2004). Endocrinology 145: 4522–4531.

  • Akhtar M, Watson JL, Nazli A, McKay DM . (2003). FASEB J 17: 1319–1321.

  • Ali A, Hoeflich KP, Woodgett JR . (2001). Chem Rev 101: 2527–2540.

  • Bancroft CC, Chen Z, Dong G, Sunwoo JB, Yeh N, Park C et al. (2001). Clin Cancer Res 7: 435–442.

  • Brew R, Erikson JS, West DC, Kinsella AR, Slavin J, Christmas SE . (2000). Cytokine 12: 78–85.

  • Brodie C, Blumberg PM . (2003). Apoptosis 8: 19–27.

  • Chen BC, Chang YS, Kang JC, Hsu MJ, Sheu JR, Chen TL et al. (2004). J Biol Chem 279: 20889–20897.

  • Choi JH, Hur J, Yoon CH, Kim JH, Lee CS, Youn SW et al. (2004). J Biol Chem 279: 49430–49438.

  • Claria J . (2003). Curr Pharm Des 9: 2177–2190.

  • Coghlan MP, Culbert AA, Cross DA, Corcoran SL, Yates JW, Pearce NJ et al. (2000). Chem Biol 7: 793–803.

  • Corbit KC, Foster DA, Rosner MR . (1999). Mol Cell Biol 19: 4209–4218.

  • Diehl JA, Cheng M, Roussel MF, Sherr CJ . (1998). Genes Dev 12: 3499–3511.

  • Ding Q, Wang Q, Evers BM . (2001). Biochem Biophys Res Commun 284: 282–288.

  • Doble BW, Woodgett JR . (2003). J Cell Sci 116: 1175–1186.

  • Eickholt BJ, Walsh FS, Doherty P . (2002). J Cell Biol 157: 211–217.

  • Fang X, Yu S, Tanyi JL, Lu Y, Woodgett JR, Mills GB . (2002). Mol Cell Biol 22: 2099–2110.

  • Fernando RI, Wimalasena J . (2004). Mol Biol Cell 15: 3266–3284.

  • Frame S, Cohen P . (2001). Biochem J 359: 1–16.

  • Ilyas M, Tomlinson IP, Rowan A, Pignatelli M, Bodmer WF . (1997). Proc Natl Acad Sci USA 94: 10330–10334.

  • Inoue H, Nanayama T, Hara S, Yokoyama C, Tanabe T . (1994). FEBS Lett 350: 51–54.

  • Jope RS, Johnson GV . (2004). Trends Biochem Sci 29: 95–102.

  • Kim JW, Lee JE, Kim MJ, Cho EG, Cho SG, Choi EJ . (2003). J Biol Chem 278: 13995–14001.

  • King WG, Mattaliano MD, Chan TO, Tsichlis PN, Brugge JS . (1997). Mol Cell Biol 17: 4406–4418.

  • Lee YJ, Soh JW, Dean NM, Cho CK, Kim TH, Lee SJ et al. (2002). Cell Growth Differ 13: 237–246.

  • Levy L, Neuveut C, Renard CA, Charneau P, Branchereau S, Gauthier F et al. (2002). J Biol Chem 277: 42386–42393.

  • Li Y, Bharti A, Chen D, Gong J, Kufe D . (1998). Mol Cell Biol 18: 7216–7224.

  • Mazor M, Kawano Y, Zhu H, Waxman J, Kypta RM . (2004). Oncogene 23: 7882–7892.

  • Minden A, Karin M . (1997). Biochim Biophys Acta 1333: F85–F104.

  • Miranti CK, Ohno S, Brugge JS . (1999). J Biol Chem 274: 10571–10581.

  • Mitsiades CS, Mitsiades N, Poulaki V, Schlossman R, Akiyama M, Chauhan D et al. (2002). Oncogene 21: 5673–5683.

  • Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B et al. (1997). Science 275: 1787–1790.

  • Murugappan S, Tuluc F, Dorsam RT, Shankar H, Kunapuli SP . (2004). J Biol Chem 279: 2360–2367.

  • Pan ZZ, Bruening W, Giasson BI, Lee VM, Godwin AK . (2002). J Biol Chem 277: 35050–35060.

  • Papadakis KA, Targan SR . (2000). Annu Rev Med 51: 289–298.

  • Park HS, Kim MS, Huh SH, Park J, Chung J, Kang SS et al. (2002). J Biol Chem 277: 2573–2578.

  • Perletti GP, Marras E, Concari P, Piccinini F, Tashjian Jr AH . (1999). Oncogene 18: 1251–1256.

  • Phiel CJ, Klein PS . (2001). Annu Rev Pharmacol Toxicol 41: 789–813.

  • Plyte SE, Hughes K, Nikolakaki E, Pulverer BJ, Woodgett JR . (1992). Biochim Biophys Acta 1114: 147–162.

  • Rao R, Hao CM, Breyer MD . (2004). J Biol Chem 279: 3949–3955.

  • Remacle-Bonnet MM, Garrouste FL, Heller S, Andre F, Marvaldi JL, Pommier GJ . (2000). Cancer Res 60: 2007–2017.

  • Rommel C, Clarke BA, Zimmermann S, Nunez L, Rossman R, Reid K et al. (1999). Science 286: 1738–1741.

  • Rossig L, Badorff C, Holzmann Y, Zeiher AM, Dimmeler S . (2002). J Biol Chem 277: 9684–9689.

  • Schaeffer HJ, Weber MJ . (1999). Mol Cell Biol 19: 2435–2444.

  • Seger R, Krebs EG . (1995). FASEB J 9: 726–735.

  • Takada Y, Fang X, Jamaluddin MS, Boyd DD, Aggarwal BB . (2004). J Biol Chem 279: 39541–39554.

  • Takahashi-Yanaga F, Shiraishi F, Hirata M, Miwa Y, Morimoto S, Sasaguri T . (2004). Biochem Biophys Res Commun 316: 411–415.

  • Tang Q, Gonzales M, Inoue H, Bowden GT . (2001). Cancer Res 61: 4329–4332.

  • Tominaga K, Higuchi K, Sasaki E, Suto R, Watanabe T, Fujiwara Y et al. (2004). Aliment Pharmacol Ther 20 (Suppl 1): 143–150.

  • Tsujio I, Tanaka T, Kudo T, Nishikawa T, Shinozaki K, Grundke-Iqbal I et al. (2000). FEBS Lett 469: 111–117.

  • Vanhaesebroeck B, Leevers SJ, Ahmadi K, Timms J, Katso R, Driscoll PC et al. (2001). Annu Rev Biochem 70: 535–602.

  • Wang Q, Ding Q, Dong Z, Ehlers RA, Evers BM . (2000). Anticancer Res 20: 75–83.

  • Wang Q, Wang X, Evers BM . (2003). J Biol Chem 278: 51091–51099.

  • Wang Q, Wang X, Hernandez A, Kim S, Evers BM . (2001). Gastroenterology 120: 1381–1392.

  • Wang Y, Schattenberg JM, Rigoli RM, Storz P, Czaja MJ . (2004). J Biol Chem 279: 31089–31097.

  • Watcharasit P, Bijur GN, Zmijewski JW, Song L, Zmijewska A, Chen X et al. (2002). Proc Natl Acad Sci USA 99: 7951–7955.

  • Wilkinson MG, Millar JB . (2000). FASEB J 14: 2147–2157.

  • Williams C, Shattuck-Brandt RL, DuBois RN . (1999). Ann NY Acad Sci 889: 72–83.

  • Wong NA, Pignatelli M . (2002). Am J Pathol 160: 389–401.

  • Zhao D, Keates AC, Kuhnt-Moore S, Moyer MP, Kelly CP, Pothoulakis C . (2001). J Biol Chem 276: 44464–44471.

  • Zimmermann S, Moelling K . (1999). Science 286: 1741–1744.

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Acknowledgements

We thank Eileen Figueroa and Karen Martin for manuscript preparation. This work was supported by Grants RO1 DK48498, R37 AG10885 and PO1 DK35608 from the National Institutes of Health.

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Authors and Affiliations

  1. Department of Surgery, The University of Texas Medical Branch, Galveston, TX, USA

    Q Wang, Y Zhou, X Wang & B M Evers

  2. The Sealy Center for Cancer Cell Biology, The University of Texas Medical Branch, Galveston, TX, USA

    B M Evers

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Correspondence to B M Evers.

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Wang, Q., Zhou, Y., Wang, X. et al. Glycogen synthase kinase-3 is a negative regulator of extracellular signal-regulated kinase. Oncogene 25, 43–50 (2006). https://doi.org/10.1038/sj.onc.1209004

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