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Regulation and function of protein kinase B and MAP kinase activation by the IL-5/GM-CSF/IL-3 receptor

Oncogene volume 18, pages 3334–3342 (1999)Cite this article

Abstract

Interleukin (IL)-3, IL-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF) regulate proliferation, differentiation and apoptosis of target cells. Receptors for these cytokines consist of a cytokine-specific α subunit and a common shared βc subunit. Tyrosine phosphorylation of the βc is thought to play a critical role in mediating signal transduction events. We have examined the effect of mutation of βc tyrosines on the activation of multiple signal transduction pathways. Activation of protein kinase B (PKB) required JAK2 and was inhibited by dominant-negative phosphatidylinositol 3-kinase (P13K). Overexpression of JAK2 was sufficient to activate both protein kinase B (PKB) and extracellular regulated kinase-1 (ERK1). Tyrosine 577 and 612 were found to be critical for the activation of PKB and ERK1, but not activation of STAT transcription factors. Activation of both PKB and ERK have been implicated in the regulation of proliferation and apoptosis. We generated GM-CSFR stable cell lines expressing receptor mutants to evaluate their effect on these processes. Activation of both PKB and ERK was perturbed, while STAT activation remained unaffected. Tyrosines 577 and 612 were necessary for optimal proliferation, however, mutation of these tyrosine residues did not affect GM-CSF mediated rescue from apoptosis. These data demonstrate that while phosphorylation of βc tyrosine residues 577 and 612 are important for optimal cell proliferation, rescue from apoptosis can be mediated by alternative signalling routes apparently independent of PKB or ERK activation.

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References

  • Ahmed NN, Grimes HL, Bellacosa A, Chan TO and Tsichlis PN. . 1997 Proc. Natl. Acad. Sci. USA 94: 3627–3632.

  • Al Shami A, Bourgoin SG and Naccache PH. . 1997 Blood 89: 1035–1044.

  • Alessi DR, Kozlowski MT, Weng QP, Morrice N and Avruch J. . 1997 Curr. Biol. 8: 69–81.

  • Anderson SM, Burton EA and Koch BL. . 1997 J. Biol. Chem. 272: 739–745.

  • Andrews NC and Faller DV. . 1991 Nucl. Acids. Res. 19: 2499.

  • Arai KI, Lee F, Miyajima A, Miyatake S, Arai N and Yakota T. . 1990 Annu. Rev. Biochem. 59: 783–786.

  • Bone H, Dechert U, Jirik F, Schrader JW and Welham MJ. . 1997 J. Biol. Chem. 272: 14470–14476.

  • Briscoe J, Rogers NC, Witthuhn BA, Watling D, Harpur AG, Wilks AF, Stark GR, Ihle JN and Kerr IM. . 1996 EMBO J. 15: 799–809.

  • Burgering BMT and Coffer PJ. . 1995 Nature 376: 599–602.

  • Caldenhoven E, Coffer P, Yuan J, Van-de-Stolpe A, Horn F, Kruijer W and Van-der-Saag PT. . 1994 J. Biol. Chem. 269: 21146–21154.

  • Caldenhoven E, van Dijk T, Raaijmakers JA, Lammers JW, Koenderman L and de Groot RP. . 1995 J. Biol. Chem. 270: 25778–25784.

  • Caldenhoven E, Van Dijk TB, Solari R, Armstrong J, Raaijmakers JAM, Lammers JWJ, Koenderman L and De Groot RP. . 1996 J. Biol. Chem. 271: 13221–13227.

  • Calvo V, Wood M, Gjertson C, Vik T and Bierer BE. . 1994 Eur. J. Immunol. 24: 2664–2671.

  • Chin H, Saito T, Arai A, Yamamoto K, Kamiyama R, Miyasaka N and Miura O. . 1997 Biochem. Biophys. Res. Commun. 239: 412–417.

  • Coffer PJ, Geijsen N, M'Rabet L, Schweizer RC, Maikoe T, Raaijmakers JAM, Lammers JWJ and Koenderman L. . 1998a Biochem. J. 329: 121–130.

  • Coffer PJ, Schweizer RC, Dubois GR, Maikoe T, Lammers JW and Koenderman L. . 1998b Blood 91: 2547–2557.

  • Corey S, Eguinoa A, Puyana-Theall K, Bolen JB, Cantley L, Mollinedo F, Jackson TR, Hawkins PT and Stephens LR. . 1993 EMBO J. 12: 2681–2690.

  • Darnell Jr JE. . 1997 Science 277: 1630–1635.

  • Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y and Greenberg ME. . 1997 Cell 91: 231–241.

  • De Groot RP, Van Dijk TB, Caldenhoven E, Coffer PJ, Raaijmakers JA, Lammers JWJ and Koenderman L. . 1997 J. Biol. Chem. 272: 2319–2325.

  • De Groot RP, Coffer PJ and Koenderman L. . 1998 Cell. Signal. In press.

  • Del Peso LM, González-Garcia M, Page C, Herrera R and Nuñez G. . 1997 Science 278: 687–689.

  • Durstin M, Inhorn RC and Griffin JD. . 1996 J. Immunol. 157: 534–540.

  • Frank SJ, Yi W, Zhao Y, Goldsmith JF, Gilliland G, Jiang J, Sakai I and Kraft AS. . 1995 J. Biol. Chem. 270: 14776–14785.

  • Franke TF, Yang SI, Chan TO, Datta K, Kazlauskas A, Morrison DK, Kaplan DR and Tsichlis PN. . 1995 Cell 81: 727–736.

  • Fried M and Crothers DM. . 1981 Nucl. Acids Res. 9: 6505–6525.

  • Gale RE, Freeburn RW, Khwaja A, Chopra R and Linch DC. . 1998 Blood 91: 54–63.

  • Gold MR, Duronio V, Saxena SP, Schrader JW and Aebersold R. . 1994 J. Biol. Chem. 269: 5403–5412.

  • Haas-Kogan D, Shalev N, Wong M, Mills G, Yount G and Stokoe D. . 1998 Curr. Biol. 8: 1195–1198.

  • Hara K, Yonezawa K, Sakaue H, Ando A, Kotani K, Kitamura T, Kitamura Y, Ueda H, Stephens L, Jackson TR, Hawkins PT, Dhand R, Clark AE, Holman GD, Waterfield GD and Kasuga M. . 1994 Proc. Natl. Acad. Sci. USA 91: 7415–7419.

  • He TC, Jiang N, Zhuang H and Wojchowski DM. . 1995 J. Biol. Chem. 270: 11055–11061.

  • Itoh T, Liu R, Yokota T, Arai KI and Watanabe S. . 1998 Mol. Cell. Biol. 18: 742–752.

  • Itoh T, Muto A, Watanabe S, Miyajima A, Yokata T and Arai K. . 1996 J. Biol. Chem. 271: 7587–7592.

  • Iversen PO, Lewis ID, Turczynowicz S, Hasle H, Niemeyer C, Schmiegelow K, Bastiras S, Biondi A, Hughes TP and Lopez AF. . 1997 Blood 90: 4910–4917.

  • Jücker M and Feldman RA. . 1995 J. Biol. Chem. 270: 27817–27822.

  • Kauffman-Zeh A, Rodriquez-Viciana P, Ulrich E, Gilbert C, Coffer P, Downward J and Evan G. . 1997 Nature 385: 544–548.

  • Kinoshita T, Shirouzu M, Kamiya A, Hashimoto K, Yokoyama S and Miyajima A. . 1997 Oncogene 15: 619–627.

  • Kulik G and Weber MJ. . 1998 Mol. Cell. Biol. 18: 6711–6718.

  • Lanfrancone L, Pelicci G, Brizzi MF, Aronica MG, Casciari C, Giuli S, Pegoraro L, Pawson T and Pelicci PG. . 1995 Oncogene 10: 907–917.

  • Lopez AF, Elliott MJ, Woodcock J and Vadas MA. . 1992 Immunol. Today 13: 495–500.

  • Meydan N, Grunberger T, Dadi H, Shahar M, Arpaia E, Lapidot Z, Leeder JS, Freedman M, Cohen A, Gazit A, Levitzki A and Roifman CM. . 1996 Nature 379: 645–648.

  • Muli AL, Wakao H, Kinoshita T, Kitamura T and Miyajima A. . 1996 EMBO J. 15: 2425–2433.

  • Odai H, Sasaki K, Iwamatsu A, Hanazono Y, Tanaka T, Mitani K, Yazaki Y and Hirai H. . 1995 J. Biol. Chem. 270: 10800–10805.

  • Okuda K, Ernst TJ and Griffin JD. . 1994 J. Biol. Chem. 269: 24602–24607.

  • Okuda K, Smith L, Griffin JD and Foster R. . 1997 Blood 90: 4759–4766.

  • Pazdrak K, Adachi T and Alam R. . 1997 J. Exp. Med. 186: 561–568.

  • Perkins GR, Marshall CJ and Collins MKL. . 1996 Blood 87: 3669–3675.

  • Polotskaya A, Zhao Y, Lilly ML and Kraft AS. . 1993 Cell Growth Diff. 4: 523–531.

  • Polotskaya A, Zhao Y, Lilly ML and Kraft AS. . 1994 J. Biol. Chem. 269: 14607–14613.

  • Pratt JC, Weiss M, Sieff CA, Shoelson SE, Burakoff SJ and Ravichandran KS. . 1996 J. Biol. Chem. 271: 12137–12140.

  • Quelle FW, Sato N, Witthuhn BA, Inhorn RC, Eder M, Miyajima A, Griffin JD and Ihle JN. . 1994 Mol. Cell. Biol. 14: 4335–4341.

  • Rivas CI, Vera JC, Delgado-Lopez F, Heaney ML, Guaiquil VH, Zhang RH, Scher HE, Concha II, Nualart F, Cordon-Cardo C and Golde DW. . 1998 Blood 91: 1037–1043.

  • Sakai I and Kraft AS. . 1997 J. Biol. Chem. 272: 12350–12358.

  • Sato N, Sakamaki K, Terada N, Arai K and Miyajima A. . 1993 EMBO J. 12: 4181–4189.

  • Scheid MP and Duronio V. . 1998 Proc. Natl. Acad. Sci. USA 95: 7439–7444.

  • Songyang Z, Baltimore D, Cantley LC, Kaplan DR and Franke TF. . 1997 Proc. Natl. Acad. Sci. USA 94: 11345–11350.

  • Stephens L, Anderson K, Stokoe D, Erdjument-Bromage H, Painter GF, Holmes AB, Gaffney PRJ, Reese CB, McCormick F, Tempst P, Coadwell J and Hawkins PT. . 1998 Science 279: 710–714.

  • Stokoe D, Stephens LR, Copeland T, Gaffney PRJ, Reese CB, Painter GF, Holmes AB, McCormick F and Hawkins PT. . 1997 Science 277: 567–570.

  • Takaki S, Kanazawa H, Shiiba M and Takatsu K. . 1994 Mol. Cell. Biol. 14: 7404–7413.

  • Tanner JW, Chen W, Young RL, Longmore GD and Shaw AS. . 1995 J. Biol. Chem. 270: 6523–6530.

  • Terada K, Kaziro Y and Satoh T. . 1995 Proc. Natl. Acad. Sci. USA 270: 27880–27886.

  • Van Dijk TB, Caldenhoven E, Raaijmakers JAM, Lammers JWJ, Koenderman L, De Groot RP. . 1997 FEBS Lett. 412: 161–164.

  • Van Weeren PC, de Bruyn KMT, de Vries-Smit AMM, van Lint J and Burgering BMT. . 1998 J. Biol. Chem. 273: 13150–13156.

  • Wei S, Liu JH, Epling-Burnette PK, Gamero AM, Ussery D, Pearson EW, Elkabani ME, Diaz JI and Djeu JY. . 1996 J. Immunol. 157: 5155–5162.

  • Welham MJ, Dechert U, Leslie KB, Jirik F and Schrader JW. . 1994 J. Biol. Chem. 269: 23764–23768.

  • Winston LA and Hunter T. . 1995 J. Biol. Chem. 270: 30837–30840.

  • Yousefi S, Hoessli DC, Blaser K, Mills GB and Simon HU. . 1996 J. Exp. Med. 183: 1407–1414.

  • Zhao Y, Wagner F, Frank SJ and Kraft AS. . 1995 J. Biol. Chem. 270: 13814–13818.

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Acknowledgements

We would like to thank Kris Reedquist for critically reading the manuscript and members of the Department of Pulmonary Diseases for valuable discussions. This work was supported by GlaxoWellcome bv.

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  1. Department of Pulmonary Diseases, University Hospital Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands

    Pascale F Dijkers, Thamar B van Dijk, Rolf P de Groot, Jan AM Raaijmakers, Jan-Willem J Lammers, Leo Koenderman & Paul J Coffer

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Dijkers, P., van Dijk, T., de Groot, R. et al. Regulation and function of protein kinase B and MAP kinase activation by the IL-5/GM-CSF/IL-3 receptor. Oncogene 18, 3334–3342 (1999). https://doi.org/10.1038/sj.onc.1202678

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