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

被引:34
作者
Chen, J
Williams, IR
Lee, BH
Duclos, N
Huntly, BJP
Donoghue, DJ
Gilliland, DG
机构
[1] Emory Univ, Sch Med, Winship Canc Ctr, Atlanta, GA 30322 USA
[2] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA
[3] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA
[4] Emory Univ, Dept Pathol, Atlanta, GA 30322 USA
[5] Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92093 USA
关键词
D O I
10.1182/blood-2004-09-3686
中图分类号
R5 [内科学];
学科分类号
1002 [临床医学]; 100201 [内科学];
摘要
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 C gamma (PLC gamma) binding and activation, significantly attenuated FGFR3 TDII-mediated PLC gamma 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 Tcell lymphomas. Moreover, 2 independent E mu SR-FGFR3 TDII-transgenic mouse lines developed a pro-B-cell lymphoma, and PLC gamma was highly activated in primary lymphoma cells as assessed by tyrosine phosphorylation. These data indicate that engagement of multiple signaling pathways, including PLC gamma-dependent and PLC gamma-independent pathways, is required for full hematopoietic transformation by constitutively activated FGFR3 mutants.
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页码:328 / 337
页数:10
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