FRMD6 inhibits human glioblastoma growth and progression by negatively regulating activity of receptor tyrosine kinases.
FRMD6 inhibits human glioblastoma growth and progression by negatively regulating activity of receptor tyrosine kinases.
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DOI：
10.18632/oncotarget.12148
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发表时间：
2016-10-25
期刊：
影响因子：
--
通讯作者：
Yu Q
中科院分区：
文献类型：
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作者：
Xu Y;Wang K;Yu Q
FRMD 6是Ezrin/Radixin/Moesin（ERM）家族蛋白，并且是果蝇扩展（ex）的人类同源物。Ex在Hippo信号通路的上游与果蝇Merlin平行发挥功能，该通路控制增殖、凋亡、组织再生和肿瘤发生。尽管Hippo通路的核心激酶级联（MST 1/2-Lats 1/2-雅普/TAZ）已经被很好地建立，但是其上游调节因子还没有被很好地理解。梅林促进河马途径的激活。然而，FRMD 6对Hippo通路的影响是有争议的。关于FRMD 6的功能以及FRMD在胶质瘤发生和胶质母细胞瘤（GBM）进展中的潜在作用知之甚少。我们首次证明FRMD 6在人GBM细胞和组织中下调，并且增加的FRMD 6表达抑制而FRMD 6敲低促进体外GBM细胞增殖/侵袭和体内GBM生长/进展。此外，我们证明，与merlin的表达增加不同，其增强了Hippo途径的应激诱导的激活，FRMD 6表达增加对该途径的影响很小。相反，我们发现FRMD 6抑制了一对受体酪氨酸激酶（RTK）的激活，包括c-Met和PDGFR及其下游的Erk和AKT激酶。此外，我们表明，组成型活性c-Met，TPR-Met融合蛋白的表达，在很大程度上逆转了FRMD 6在体内的抗GBM作用，这表明FRMD 6的功能至少部分通过抑制RTK，特别是c-Met的活性。这些结果确立了FRMD 6在抑制人GBM生长和进展中的新功能，并揭示了FRMD 6发挥其抗GBM活性的新机制。
FRMD6 is an Ezrin/Radixin/Moesin (ERM) family protein and a human homologue of Drosophila expanded (ex). Ex functions in parallel of Drosophila merlin at upstream of the Hippo signaling pathway that controls proliferation, apoptosis, tissue regeneration, and tumorigenesis. Even though the core kinase cascade (MST1/2-Lats1/2-YAP/TAZ) of the Hippo pathway has been well established, its upstream regulators are not well understood. Merlin promotes activation of the Hippo pathway. However, the effect of FRMD6 on the Hippo pathway is controversial. Little is known about how FRMD6 functions and the potential role of FRMD in gliomagenesis and glioblastoma (GBM) progression. We demonstrate for the first time that FRMD6 is down-regulated in human GBM cells and tissues and that increased FRMD6 expression inhibits whereas FRMD6 knockdown promotes GBM cell proliferation/invasion in vitro and GBM growth/progression in vivo. Furthermore, we demonstrate that unlike increased expression of merlin, which enhances the stress induced activation of the Hippo pathway, increased FRMD6 expression displays little effect on the pathway. In contrast, we show that FRMD6 inhibits activation of a couple of receptor tyrosine kinases (RTKs) including c-Met and PDGFR and their downstream Erk and AKT kinases. Moreover, we show that expression of constitutively active c-Met, the TPR-Met fusion protein, largely reverses the anti-GBM effect of FRMD6 in vivo, suggesting that FRMD6 functions at least partially through inhibiting activity of RTKs especially c-Met. These results establish a novel function of FRMD6 in inhibiting human GBM growth and progression and uncover a novel mechanism by which FRMD6 exerts its anti-GBM activity.