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Signal transduction by several KIT juxtamembrane domain mutations

Oncogene volume 22, pages 4710–4722 (2003)Cite this article

Abstract

Mutations of KIT receptor tyrosine kinase are found in the majority of patients with mastocytosis and in most gastrointestinal stromal tumors. Oncogenic KIT mutations in GISTs are located in the KIT juxtamembrane domain (JMD), while codon 816 in the KIT kinase domain is mutated in systemic mastocytosis. We describe and characterize a mutation in the KIT-JMD named KΔ27. We show that KΔ27 mutant is constitutively dimerized and phosphorylated. KΔ27 ectopic expression renders both the Ba/F3 cell line and primary cultures of bone marrow mast cells independent of cytokines for proliferation and cell survival. The classical signaling pathways activated by wild-type KIT upon ligand stimulation are constitutively activated by KΔ27 and other JMD mutations. However, a side-to-side comparison revealed differences between the wild-type and JMD mutations. First, in vitro kinase assays reveal a change in peptide substrate specificity. Second, STAT proteins are preferentially phosphorylated by KIT mutants. Third, inhibitors of KIT kinase are more efficient on JMD mutations than on WT KIT. We conclude that KΔ27 is a new oncogenic KIT mutation showing constitutive activation of downstream signaling pathways, and suggest that specific pathways are activated by oncogenic KIT.

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References

  • Beghini A, Cairoli R, Morra E and Larizza L . (1998). Blood Cells Mol. Dis., 24, 262–270.

  • Beghini A, Peterlongo P, Ripamonti CB, Larizza L, Cairoli R, Morra E and Mecucci C . (2000). Blood, 95, 726–772.

  • Berra E, Diaz-Meco MT and Moscat J . (1998). J Biol Chem, 273, 10792–10797.

  • Beslu N, Larose J, Casteran N, Birnbaum D, Lecocq E, Dubreuil P and Rottapel R . (1996). J. Biol. Chem., 271, 20075–20081.

  • Blume-Jensen P, Janknecht R and Hunter T . (1998). Curr Biol., 8, 779–782.

  • Brizzi MF, Dentelli P, Rosso A, Yarden Y and Pegoraro L . (1999). J. Biol. Chem., 274, 16965–16972.

  • Casteran N, Beslu N, Lecocq E, Gomez S and Dubreuil P . (1998). Leukemia, 12, 1089–1098.

  • Chian R, Young S, Danilkovitch-Miagkova A, Ronnstrand L, Leonard E, Ferrao P, Ashman L and Linnekin D . (2001). Blood, 98, 1365–1373.

  • Dastych J and Metcalfe DD . (1994). J. Immunol., 152, 213–219.

  • Frost MJ, Ferrao PT, Hughes TP and Ashman LK . (2002). Mol. Cancer Ther., 1, 1115–1124.

  • Furitsu T, Tsujimura T, Tono T, Ikeda H, Kitayama H, Koshimizu U, Sugahara H, Butterfield JH, Ashman LK, Kanayama Y, Matsuzawa Y, Kitamura Y and Kanakura Y . (1993). J. Clin. Invest., 92, 1736–1744.

  • Gurish MF, Ghildyal N, McNeil HP, Austen KF, Gillis S and Stevens RL . (1992). J. Exp. Med., 175, 1003–1012.

  • Herbst R, Munemitsu S and Ullrich A . (1995). Oncogene, 10, 369–379.

  • Hibi K, Takahashi T, Sekido Y, Ueda R, Hida T, Ahiyoshi Y, Takagi H and Takahashi T . (1991). Oncogene, 6, 2291–2296.

  • Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, Kawano K, Hanada M, Kurata A, Takeda M, Muhammad Tunio G, Matsuzawa Y, Kanakura Y, Shinomura Y and Kitamura Y . (1998). Science, 279, 577–580.

  • Irusta PM and DiMaio D . (1998). EMBO. J., 17, 6912–6923.

  • Jeffers M, Schmidt L, Nakaigawa N, Webb CP, Weirich G, Kishida T, Zbar B and Vande Woude GF . (1997). Proc. Natl. Acad. Sci. USA, 94, 11445–11450.

  • Jin L, Asano H and Blau CA . (1998). Blood, 91, 890–897.

  • Kinashi T and Springer TA . (1994). Blood, 83, 1033–1038.

  • Kitayama H, Kanakura Y, Furitsu T, Tsujimura T, Oritani K, Ikeda H, Sugahara H, Mitsui H, Kanayama Y, Kitamura Y, and Matsuzawa Y . (1995). Blood, 85, 790–798.

  • Kitayama H, Tsujimura T, Matsumura I, Oritani K, Ikeda H, Ishikawa J, Okabe M, Suzuki M, Yamamura K, Matsuzawa Y, Kitamura Y and Kanakura Y . (1996). Blood, 88, 995–1004.

  • Kozlowski M, Larose L, Lee F, Le DM, Rottapel R and Siminovitch KA . (1998). Mol. Cell. Biol., 18, 2089–2099.

  • Krystal GW, Carlson P and Litz J . (1997). Cancer Res, 57, 2203–2208.

  • Krystal GW, Honsawek S, Litz J and Buchdunger E . (2000). Clin. Cancer Res., 6, 3319–3326.

  • Leslie NR, O'Prey J, Bartholomew C and Harrison PR . (1998). Blood, 92, 4798–4807.

  • Linnekin D, DeBerry CS and Mou S . (1997). J. Biol. Chem., 272, 27450–27455.

  • London CA, Galli SJ, Yuuki T, Hu ZQ, Helfand SC and Geissler EN . (1999). Exp. Hematol., 27, 689–697.

  • Longley BJ, Reguera MJ and Ma Y . (2001). Leuk. Res., 25, 571–576.

  • Longley BJ, Tyrrell L, Lu SZ, Ma YS, Langley K, Ding TG, Duffy T, Jacobs P, Tang LH and Modlin I . (1996). Nat. Genet., 12, 312–314.

  • Ma Y, Cunningham ME, Wang X, Ghosh I, Regan L and Longley BJ . (1999a). J. Biol. Chem., 274, 13399–13402.

  • Ma Y, Longley BJ, Wang X, Blount JL, Langley K and Caughey GH . (1999b). J. Invest. Dermatol., 112, 165–170.

  • Moriyama Y, Tsujimura T, Hashimoto K, Morimoto M, Kitayama H, Matsuzawa Y, Kitamura Y and Kanakura Y . (1996). J. Biol. Chem., 271, 3347–3350.

  • Nagata H, Worobec AS, Oh CK, Chowdhury BA, Tannenbaum S, Suzuki Y and Metcalfe DD . (1995). Proc. Natl. Acad. Sci. USA, 92, 10560–10564.

  • Nakao M, Yokota S, Iwai T, Kaneko H, Horiike S, Kashima K, Sonoda Y, Fujimoto T and Misawa S . (1996). Leukemia, 10, 1911–1918.

  • Ning ZQ, Li J and Arceci RJ . (2001). Blood, 97, 3559–3567.

  • Piao X and Bernstein A . (1996). Blood, 87, 3117–3123.

  • Piao X, Paulson R, van der Geer P, Pawson T and Bernstein A . (1996). Proc. Natl. Acad. Sci. USA, 93, 14665–14669.

  • Pignon JM, Giraudier S, Duquesnoy P, Jouault H, Imbert M, Vainchenker W, Vernant JP and Tulliez M . (1997). Br. J. Haematol., 96, 374–376.

  • Price DJ, Rivnay B, Fu Y, Jiang S, Avraham S and Avraham H . (1997). J. Biol. Chem., 272, 5915–5920.

  • Qiu FH, Ray P, Brown K, Barker PE, Jhanwar S, Ruddle FH and Besmer P . (1988). EMBO J., 7, 1003–1011.

  • Reith AD, Ellis C, Lyman SD, Anderson DM, Williams DE, Bernstein A and Pawson T . (1991). EMBO J., 10, 2451–2459.

  • Rosnet O and Birnbaum D . (1993). Crit. Rev. Oncog., 4, 595–613.

  • Rottapel R, Reedijk M, Williams DE, Lyman SD, Anderson DM, Pawson T and Bernstein A . (1991). Mol. Cell. Biol., 11, 3043–3051.

  • Rottapel R, Turck CW, Casteran N, Liu X, Birnbaum D, Pawson T and Dubreuil P . (1994). Oncogene, 9, 1755–1765.

  • Santoro M, Carlomagno F, Romano A, Bottaro DP, Dathan NA, Grieco M, Fusco A, Vecchio G, Matoskova B, Kraus MH and Di Fiore PP . (1995). Science, 267, 381–383.

  • Serve H, Yee NS, Stella G, Sepp LL, Tan JC and Besmer P . (1995). EMBO J., 14, 473–483.

  • Sperr WR, Walchshofer S, Horny HP, Fodinger M, Simonitsch I, Fritsche-Polanz R, Schwarzinger I, Tschachler E, Sillaber C, Hagen W, Geissler K, Chott A, Lechner K and Valent P . (1998). Br. J. Haematol., 103, 740–749.

  • Taniguchi M, Nishida T, Hirota S, Isozaki K, Ito T, Nomura T, Matsuda H and Kitamura Y . (1999). Cancer Res., 59, 4297–4300.

  • Tsujimura T, Furitsu T, Morimoto M, Isozaki K, Nomura S, Matsuzawa Y, Kitamura Y and Kanakura Y . (1994). Blood, 83, 2619–2626.

  • Tsujimura T, Hashimoto K, Kitayama H, Ikeda H, Sugahara H, Matsumura I, Kaisho T, Terada N, Kitamura Y and Kanakura Y . (1999). Blood, 93, 1319–1329.

  • Tsujimura T, Kanakura Y and Kitamura Y . (1997). Leukemia, 11, (Suppl 3), 396–398.

  • Tsujimura T, Morimoto M, Hashimoto K, Moriyama Y, Kitayama H, Matsuzawa Y, Kitamura Y and Kanakura Y . (1996). Blood, 87, 273–283.

  • Zermati Y, De Sepulveda P, Feger F, Letard S, Kersual J, Casteran N, Gorochov G, Dy M, Ribadeau Dumas A, Dorgham K, Parizot C, Bieche Y, Vidaud M, Lortholary O, Arock M, Hermine O and Dubreuil P . (2003). Oncogene, 22, 660–664.

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Acknowledgements

NC and NB were recipients of ARC fellowships. SL is a recipient of an AFIRMM (Association Française pour les Initiatives de Recherche sur le Mastocyte et les Mastocytoses) fellowship. Our laboratory is funded by INSERM and La Ligue Nationale Centre le Cancer.

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Author notes

  1. Nathalie Casteran and Paulo De Sepulveda: NC and PDS contributed equally to this work.

Authors and Affiliations

  1. Molecular and Functional Hematopoiesis Laboratory, U119 INSERM, 27 Bd Leï Roure, Marseille, 13009, France

    Nathalie Casteran, Paulo De Sepulveda, Nathalie Beslu, Mustapha Aoubala, Sébastien Letard, Eric Lecocq & Patrice Dubreuil

  2. Division of Experimental Therapeutics, Ontario Cancer Institute, 610 University Ave, Toronto, M5G 2M9, Ontario, Canada

    Robert Rottapel

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  1. Nathalie Casteran
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Correspondence to Paulo De Sepulveda.

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Casteran, N., De Sepulveda, P., Beslu, N. et al. Signal transduction by several KIT juxtamembrane domain mutations. Oncogene 22, 4710–4722 (2003). https://doi.org/10.1038/sj.onc.1206587

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