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Chen, J. et al.

Chen, Williams, Lee, Duclos, Huntly, Donoghue, Gilliland,

Constitutively activated FGFR3 mutants signal through PLCgamma-dependent and -independent pathways for hematopoietic transformation.

Ectopic expression of fibroblast growth factor receptor 3 ( FGFR3) associated with t(4;14) has been implicated in the pathogenesis of human multiple myeloma. Some t(4;14) patients have activating mutations of FGFR3, of which a minority are K650E (thanatophoric dysplasia type II [TDII]). To investigate the role of autophosphorylated tyrosine residues in FGFR3 signal transduction and transformation, we characterized a series of FGFR3 TDII mutants with single or multiple Y-->F substitutions. Phenylalanine substitution of Y760, essential for phospholipase Cgamma (PLCgamma) binding and activation, significantly attenuated FGFR3 TDII- mediated PLCgamma activation, as well as transformation in Ba/F3 cells and a murine bone marrow transplant leukemia model. In contrast, single substitution of Y577, Y724, or Y770 had minimal to moderate effects on TDII-dependent transformation. Substitution of all 4 non-activation loop tyrosine residues significantly attenuated, but did not abolish, TDII transforming activity. Similar observations were obtained in the context of a constitutively activated fusion TEL- FGFR3 associated with t(4;12)(p16;p13) peripheral T-cell lymphomas. Moreover, 2 independent EmuSR- FGFR3 TDII transgenic mouse lines developed a pro-B-cell lymphoma, and PLCgamma was highly activated in primary lymphoma cells as assessed by tyrosine phosphorylation. These data indicate that engagement of multiple signaling pathways, including PLCgamma-dependent and PLCgamma-independent pathways, is required for full hematopoietic transformation by constitutively activated FGFR3 mutants.[1]

References

Constitutively activated FGFR3 mutants signal through PLCgamma-dependent and -independent pathways for hematopoietic transformation. Chen, J., Williams, I.R., Lee, B.H., Duclos, N., Huntly, B.J., Donoghue, D.J., Gilliland, D.G. Blood (2005) [Pubmed]

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