Signal transducers and activators of transcription-3 binding to the fibroblast growth factor receptor is activated by receptor amplification.
Signal transducers and activators of transcription-3 binding to the fibroblast growth factor receptor is activated by receptor amplification.
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DOI：
10.1158/0008-5472.can-09-3033
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发表时间：
2010-04-15
期刊：
影响因子：
11.2
通讯作者：
Heath JK
中科院分区：
文献类型：
--
作者：
Dudka AA;Sweet SM;Heath JK
成纤维细胞生长因子受体 (FGFR) 是细胞表面酪氨酸激酶，在细胞增殖和分化中发挥作用。由于基因扩增，FGFR 信号传导异常出现在多种癌症中，但相关的致癌机制尚不清楚。使用蛋白质组学方法，我们将 STAT3 鉴定为受体结合伴侣，由 FGFR 上的 Tyr677 磷酸化介导。与激活的 FGFR 的结合对于随后的酪氨酸磷酸化和 STAT3 的核转位以及其下游靶基因的激活至关重要。 STAT3 的酪氨酸磷酸化还依赖于 SRC 和 JAK 激酶伴随的 FGFR 依赖性活性。最后，STAT3 的酪氨酸（而非丝氨酸）磷酸化需要放大的 FGFR 蛋白表达，这种表达要么是通过强制过度表达，要么与癌细胞中的基因扩增相关。我们的研究结果表明，扩增的 FGFR 表达参与 STAT3 通路，并且他们提出了攻击 FGFR 过度表达癌症的治疗策略。
Fibroblast growth factor receptors (FGFRs) are cell surface tyrosine kinases that function in cell proliferation and differentiation. Aberrant FGFR signaling occurs in diverse cancers due to gene amplification, but the associated oncogenic mechanisms are poorly understood. Using a proteomics approach, we identified STAT3 as a receptor binding partner that is mediated by Tyr677 phosphorylation on FGFR. Binding to activated FGFR was essential for subsequent tyrosine phosphorylation and nuclear translocation of STAT3, along with activation of its downstream target genes. Tyrosine phosphorylation of STAT3 was also dependent upon concomitant FGFR-dependent activity of SRC and JAK kinases. Lastly, tyrosine (but not serine) phosphorylation of STAT3 required amplified FGFR protein expression, generated either by enforced overexpression or as associated with gene amplification in cancer cells. Our findings show that amplified FGFR expression engages the STAT3 pathway, and they suggest therapeutic strategies to attack FGFR-overexpressing cancers.