Constitutively activated FGFR3 mutants signal through PLCγ-dependent and -independent pathways for hematopoietic transformation
Constitutively activated FGFR3 mutants signal through PLCγ-dependent and -independent pathways for hematopoietic transformation
复制标题
DOI：
10.1182/blood-2004-09-3686
复制
发表时间：
2005-07-01
期刊：
影响因子：
20.3
通讯作者：
Gilliland, DG
中科院分区：
文献类型：
--
作者：
Chen, J;Williams, IR;Gilliland, DG
与t(4；14)相关的成纤维细胞生长因子受体3(FGFR3)的异位表达与人类多发性骨髓瘤的发病机制有关。一些t(4；14)患者存在FGFR3激活突变，其中少数是K650E(致死性非典型增生II型[TDII])。为了研究自身磷酸化的酪氨酸残基在FGFR3信号转导和转化中的作用，我们鉴定了一系列具有单个或多个Y->；F替换的FGFR3 TDII突变体。Y760的苯丙氨酸取代对磷脂酶C-γ(PLC-γ)的结合和激活是必不可少的，它显著减弱了FGFR3-TDII介导的PLC-γ的激活，以及在BA/F3细胞和小鼠骨髓移植白血病模型中的转化。相比之下，Y577、Y724或Y770的单一替换对依赖TDII的转化有轻微到中等的影响。所有4个非激活环酪氨酸残基的替换显著减弱了TDII的转化活性，但没有取消。在与t(4；12)(p16；p13)外周T细胞淋巴瘤相关的结构性激活的TEL-FGFR3融合中也得到了类似的观察结果。此外，2个独立的E-MU SR-FGFR3 TDII转基因小鼠系发生了亲B细胞淋巴瘤，通过酪氨酸磷酸化检测，PLC-γ在原代淋巴瘤细胞中高度激活。这些数据表明，结构性激活的FGFR3突变体需要多个信号通路的参与，包括PLC伽马依赖和PLC伽马不依赖的通路，以实现完整的造血转化。
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.