FGFR1 cleavage and nuclear translocation regulates breast cancer cell behavior.
FGFR1 cleavage and nuclear translocation regulates breast cancer cell behavior.
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DOI：
10.1083/jcb.201108077
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发表时间：
2012-06-11
期刊：
影响因子：
--
通讯作者：
Grose R
中科院分区：
文献类型：
--
作者：
Chioni AM;Grose R
FGFR 1被颗粒酶B切割诱导其核转位，其中它通过对基因表达的影响刺激细胞迁移。FGF-10及其受体FGFR 1和FGFR 2与乳腺癌易感性和进展有关，表明成纤维细胞生长因子（FGF）信号传导可能被乳腺癌细胞吸收。我们确定了FGFR 1激活下游的一种新途径，由此受体被切割并运输到细胞核，在那里它可以调节特定的靶基因。我们确认颗粒酶B（GrB）作为负责切割的蛋白酶，并表明阻断GrB活性可阻止FGFR 1向细胞核的运输，并消除FGF刺激的促迁移作用。我们证实了我们的研究结果的体内相关性，表明FGFR 1定位于细胞核，特别是在乳腺癌的临床材料和三维模型中的入侵细胞。我们确定了FGFR 1的靶基因，它对细胞迁移产生显著影响，并可能代表一种侵入性特征。我们的实验确定了一种新的机制，FGF信号可以调节癌细胞的行为，并提供了一个新的治疗靶点治疗浸润性乳腺癌。
FGFR1 cleavage by Granzyme B induces its nuclear translocation, in which it stimulates cell migration through effects on gene expression. FGF-10 and its receptors, FGFR1 and FGFR2, have been implicated in breast cancer susceptibility and progression, suggesting that fibroblast growth factor (FGF) signaling may be co-opted by breast cancer cells. We identify a novel pathway downstream of FGFR1 activation, whereby the receptor is cleaved and traffics to the nucleus, where it can regulate specific target genes. We confirm Granzyme B (GrB) as the protease responsible for cleavage and show that blocking GrB activity stopped FGFR1 trafficking to the nucleus and abrogates the promigratory effect of FGF stimulation. We confirm the in vivo relevance of our findings, showing that FGFR1 localized to the nucleus specifically in invading cells in both clinical material and a three-dimensional model of breast cancer. We identify target genes for FGFR1, which exert significant effects on cell migration and may represent an invasive signature. Our experiments identify a novel mechanism by which FGF signaling can regulate cancer cell behavior and provide a novel therapeutic target for treatment of invasive breast cancer.
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