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Roles of tyrosine residues 845, 892 and 922 in constitutive activation of murine FLT3 kinase domain mutant.

Ishiko J, Mizuki M, Matsumura I, Shibayama H, Sugahara H, Scholz G, Serve H, Kanakura Y

1Department of Hematology and Oncology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.

FLT3 tyrosine kinase domain (TKD) mutations are detected in approximately 7% of acute myeloid leukemia patients, and suggested to correlate with poor prognosis and confer resistance to FLT3 inhibitors. To explore activation mechanism of FLT3 TKD mutation, we analysed critical tyrosine residues for the constitutive activation and downstream signaling of the mutant by generating a series of single Tyr --> Phe substitution mutant of all 22 cytoplasmic tyrosine residues of murine FLT3 TKD-mutant (mFLT3(Asp838Val)). Tyr845Phe, Tyr892Phe and Tyr922Phe substitutions suppressed the phosphorylation of mFLT3(Asp838Val) itself, the activation of Erk1/2, STAT3 and STAT5, and the factor-independent cell proliferation and survival. In contrast, these three Tyr --> Phe mutations partially suppressed but maintained the ligand-dependent activation and anti-apoptotic activity of wild-type FLT3, suggesting that these tyrosine residues were more critical for the constitutive activation and signaling of mFLT3(Asp838Val). These three Tyr --> Phe mutations also inhibited the constitutive activation of other FLT3 mutants bearing internal tandem duplication, Asp838Tyr or Ile839del. The suppression of mFLT3(Asp838Val) activation and signaling by these substitutions was partially recovered by shifting the culture temperature from 37 to 33 degrees C, or by the introduction of Cdc37 and Hsp90. Taken together, Tyr(845), Tyr(892) and Tyr(922) are the critical residues in mFLT3(Asp838Val) activation, possibly through stabilizing the active conformation of mFLT3(Asp838Val).Oncogene advance online publication, 1 August 2005; doi:10.1038/sj.onc.1208957.

Published 10 August 2005 in Oncogene.
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