Abstract
Activating mutations of c-kit at codon 816 (Asp816) have been identified in variety of malignancies, including acute myeloid leukemia (AML), mastocytosis and germ cell tumors. The mutant c-Kit receptor confers cytokine independence and induces tumorigenicity. However, the molecular mechanisms, particularly the changes in the signal transduction pathways, responsible for these biological effects induced by mutant c-Kit are largely undefined. Using the human embryonic kidney cell line, 293, we show in the current report that constitutive activation of STAT3 and STAT1 is associated with D816H mutant c-Kit. Transfection of dominant negative STAT3, but not STAT1 inhibits mutant c-Kit mediated anchorage-independent growth in vitro and tumor formation in vivo. Expression of constitutively activated STAT3 restores the mutant c-Kit receptor's transforming ability in 293 cells. These results demonstrate that activation of STAT3 by Asp816 mutant c-Kit is required for the anchorage-independent growth and tumorigenicity induced by Asp816 mutant c-Kit.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Alexander WS, Lyman SD, Wagner EF . 1991 EMBO J. 10: 3683–3691
Arrick BA, Lopez AR, Elfman F, Ebner R, Damsky CH, Derynck R . 1992 J. Cell. Biol. 118: 715–726
Ashman LK, Ferrao P, Cole SR, Cambareri AC . 1999 Leuk. Lymphoma 34: 451–461
Beghini A, Peterlongo P, Ripamonti CB, Larizza L, Cairoli R, Morra E, Mecucci C . 2000 Blood 95: 726–727
Bowman T, Garcia R, Turkson J, Jove R . 2000 Oncogene 19: 2474–2488
Bromberg J, Darnell Jr JE . 2000 Oncogene 19: 2468–2473
Bromberg JF, Horvath CM, Besser D, Lathem WW, Darnell Jr JE . 1998 Mol. Cell. Biol. 18: 2553–2558
Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C, Darnell Jr JE . 1999 Cell 98: 295–303
Caruana G, Cambareri AC, Ashman LK . 1999 Oncogene 18: 5573–5581
Caruana G, Cambareri AC, Gonda TJ, Ashman LK . 1998 Oncogene 16: 179–190
Catlett-Falcone R, Landowski TH, Oshiro MM, Turkson J, Levitzki A, Savino R, Ciliberto G, Moscinski L, Fernandez-Luna JL, Nunez G, Dalton WS, Jove R . 1999 Immunity 10: 105–115
Crosier PS, Ricciardi ST, Hall LR, Vitas MR, Clark SC, Crosier KE . 1993 Blood 82: 1151–1158
Darnell Jr JE . 1997 Science 277: 1630–1635
de Groot RP, Raaijmakers JA, Lammers JW, Jove R, Koenderman L . 1999 Blood 94: 1108–1112
Ferrao P, Gonda TJ, Ashman LK . 1997 Blood 90: 4539–4552
Flanagan JG, Leder P . 1990 Cell 63: 185–194
Freedman VH, Shin SI . 1974 Cell 3: 355–359
Fukada T, Ohtani T, Yoshida Y, Shirogane T, Nishida K, Nakajima K, Hibi M, Hirano T . 1998 EMBO J. 17: 6670–6677
Furitsu T, Tsujimura T, Tono T, Ikeda H, Kitayama H, Koshimizu U, Sugahara H, Butterfield JH, Ashman LK, Kanayama Y et al . 1993 J. Clin. Invest. 92: 1736–1744
Graham FL, Smiley J, Russell WC, Nairn R . 1977 J. Gen. Virol. 36: 59–74
Hashimoto K, Tsujimura T, Moriyama Y, Yamatodani A, Kimura M, Tohya K, Morimoto M, Kitayama H, Kanakura Y, Kitamura Y . 1996 Am. J. Pathol. 148: 189–200
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, Kitamura Y . 1998 Science 279: 577–580
Huang E, Nocka K, Beier DR, Chu TY, Buck J, Lahm HW, Wellner D, Leder P, Besmer P . 1990 Cell 63: 225–233
Hunter MG, Avalos BR . 2000 Blood 95: 2132–2137
Jeffers M, Schmidt L, Nakaigawa N, Webb CP, Weirich G, Kishida T, Zbar B, Vande Woude GF . 1997 Proc. Natl. Acad. Sci. USA 94: 11445–11450
Kanakura Y, Furitsu T, Tsujimura T, Butterfield JH, Ashman LK, Ikeda H, Kitayama H, Kanayama Y, Matsuzawa Y, Kitamura Y . 1994 Leukemia 8: Suppl 1 S18–22
Kitayama H, Kanakura Y, Furitsu T, Tsujimura T, Oritani K, Ikeda H, Sugahara H, Mitsui H, Kanayama Y, Kitamura Y et al . 1995 Blood 85: 790–798
Kiuchi N, Nakajima K, Ichiba M, Fukada T, Narimatsu M, Mizuno K, Hibi M, Hirano T . 1999 J. Exp. Med. 189: 63–73
Leslie NR, O'Prey J, Bartholomew C, Harrison PR . 1998 Blood 92: 4798–4807
Linnekin D . 1999 Int. J. Biochem. Cell Biol. 31: 1053–1074
Longley Jr BJ, Metcalfe DD, Tharp M, Wang X, Tyrrell L, Lu SZ, Heitjan D, Ma Y . 1999 Proc. Natl. Acad. Sci. USA 96: 1609–1614
Longley BJ, Tyrrell L, Lu SZ, Ma YS, Langley K, Ding TG, Duffy T, Jacobs P, Tang LH, Modlin I . 1996 Nat. Genet. 12: 312–314
MacAuley A, Pawson T . 1988 J. Virol. 62: 4712–4721
Moriyama Y, Tsujimura T, Hashimoto K, Morimoto M, Kitayama H, Kitamura Y, Kanakura Y . 1996 J. Biol. Chem. 271: 3347–3350
Nagata H, Worobec AS, Oh CK, Chowdhury BA, Tannenbaum S, Suzuki Y, Metcalfe DD . 1995 Proc. Natl. Acad. Sci. USA 92: 10560–10564
Nakajima K, Yamanaka Y, Nakae K, Kojima H, Ichiba M, Kiuchi N, Kitaoka T, Fukada T, Hibi M, Hirano T . 1996 EMBO J. 15: 3651–3658
Ning ZQ, Li J, Arceci RJ . 2001a Leuk. Lymphoma in press
Ning ZQ, Li J, Arceci RJ . 2001b Blood 97: 3559–3567
Piao X, Bernstein A . 1996 Blood 87: 3117–3123
Pietra D, Bressan A, Pezzotti AR, Serlupi-Crescenzi O . 1998 Gene 213: 119–124
Qiu FH, Ray P, Brown K, Barker PE, Jhanwar S, Ruddle FH, Besmer P . 1988 EMBO J. 7: 1003–1111
Schindler C, Fu XY, Improta T, Aebersold R, Darnell Jr JE . 1992 Proc. Natl. Acad. Sci. USA 89: 7836–7839
Tian Q, Frierson Jr HF, Krystal GW, Moskaluk CA . 1999 Am. J. Pathol. 154: 1643–1647
Tsai YT, Su YH, Fang SS, Huang TN, Qiu Y, Jou YS, Shih HM, Kung HJ, Chen RH . 2000 Mol. Cell. Biol. 20: 2043–2054
Tsujimura T, Furitsu T, Morimoto M, Isozaki K, Nomura S, Matsuzawa Y, Kitamura Y, Kanakura Y . 1994 Blood 83: 2619–2626
Tsujimura T, Furitsu T, Morimoto M, Kanayama Y, Nomura S, Matsuzawa Y, Kitamura Y, Kanakura Y . 1995 Int. Arch. Allergy Immunol. 106: 377–385
Turkson J, Bowman T, Garcia R, Caldenhoven E, De Groot RP, Jove R . 1998 Mol. Cell. Biol. 18: 2545–2552
Ullrich A, Schlessinger J . 1990 Cell 61: 203–212
Wagner BJ, Hayes TE, Hoban CJ, Cochran BH . 1990 EMBO J. 9: 4477–4484
Williams DE, Eisenman J, Baird A, Rauch C, Van Ness K, March CJ, Park LS, Martin U, Mochizuki DY, Boswell HS et al . 1990 Cell 63: 167–174
Wooten DK, Xie X, Bartos D, Busche RA, Longmore GD, Watowich SS . 2000 J. Biol. Chem. 275: 26566–26575
Yajima T, Kanda T, Yoshiike K, Kitamura Y . 1998 Hum. Gene. Ther. 9: 779–787
Yarden Y, Kuang WJ, Yang-Feng T, Coussens L, Munemitsu S, Dull TJ, Chen E, Schlessinger J, Francke U, Ullrich A . 1987 EMBO J. 6: 3341–3351
Yokota S, Kiyoi H, Nakao M, Iwai T, Misawa S, Okuda T, Sonoda Y, Abe T, Kahsima K, Matsuo Y, Naoe T . 1997 Leukemia 11: 1605–1609
Zong CS, Zeng L, Jiang Y, Sadowski HB, Wang LH . 1998 J. Biol. Chem. 273: 28065–28072
Zsebo M, Williams DA, Geissler EN, Broudy VC, Martin FH, Atkins HL, Hsu RY, Birkett NC, Okino KH, Murdock DC et al . 1990 Cell 63: 213–224
Acknowledgements
This work was supported by the Fellowship Award from Leukemia Research Foundation to Z-Q Ning and institutional grants to RJ Arceci.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Ning, ZQ., Li, J., McGuinness, M. et al. STAT3 activation is required for Asp816 mutant c-Kit induced tumorigenicity. Oncogene 20, 4528–4536 (2001). https://doi.org/10.1038/sj.onc.1204590
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1204590
Keywords
This article is cited by
-
SRC-like adaptor protein 2 (SLAP2) is a negative regulator of KIT-D816V-mediated oncogenic transformation
Scientific Reports (2018)
-
Cooperating gene mutations in acute myeloid leukemia: a review of the literature
Leukemia (2008)
-
Juxtamembrane-type c-kit gene mutation found in aggressive systemic mastocytosis induces imatinib-resistant constitutive KIT activation
Laboratory Investigation (2007)
-
Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment
Nature Reviews Immunology (2007)
-
KIT oncogenic signaling mechanisms in imatinib-resistant gastrointestinal stromal tumor: PI3-kinase/AKT is a crucial survival pathway
Oncogene (2007)