The actin cross-linker Filamin/Cheerio mediates tumor malignancy downstream of JNK signaling
The actin cross-linker Filamin/Cheerio mediates tumor malignancy downstream of JNK signaling
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DOI：
10.1242/jcs.114462
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发表时间：
2013-02-15
影响因子：
4
通讯作者：
Uhlirova, Mirka
中科院分区：
文献类型：
--
作者：
Kuelshammer, Eva;Uhlirova, Mirka
细胞的形状动力学、运动性和细胞增殖都依赖于肌动蛋白细胞骨架。恶性癌细胞劫持肌动蛋白网络生长并迁移到次要部位。因此，了解肌动蛋白调节子的功能是非常重要的。在本研究中，我们确定肌动蛋白交联蛋白细丝蛋白/Cheerio（雪儿）作为恶性肿瘤的遗传定义的果蝇肿瘤的介质。我们发现，在侵袭性肿瘤，从合作的激活Ras与破坏上皮细胞极性，雪儿是上调的Jun N-末端激酶（JNK）依赖的方式。尽管雪儿在正常上皮中是可有可无的，但肿瘤细胞的生长和侵袭性却需要雪儿。当失去雪儿时，这些肿瘤克隆失去了增殖和突破组织边界的全部潜力。相反，Cher缺陷型克隆仍然局限在其来源上皮细胞的范围内，允许宿主动物存活。通过与肌球蛋白II重链亚基的相互作用，雪儿可能会加强皮质肌动球蛋白网络，并加强侵袭性肿瘤内的机械张力。因此，肿瘤组织中Hippo/Yorkie信号传导下游基因的异常表达需要Cher。我们的研究将Cher确定为JNK信号转导的新靶点，该信号转导将细胞骨架动力学与肿瘤进展联系起来。
Cell shape dynamics, motility, and cell proliferation all depend on the actin cytoskeleton. Malignant cancer cells hijack the actin network to grow and migrate to secondary sites. Understanding the function of actin regulators is therefore of major interest. In the present study, we identify the actin cross-linking protein Filamin/Cheerio (Cher) as a mediator of malignancy in genetically defined Drosophila tumors. We show that in invasive tumors, resulting from cooperation of activated Ras with disrupted epithelial cell polarity, Cher is upregulated in a Jun N-terminal kinase (JNK)-dependent manner. Although dispensable in normal epithelium, Cher becomes required in the tumor cells for their growth and invasiveness. When deprived of Cher, these tumor clones lose their full potential to proliferate and breach tissue boundaries. Instead, the Cher-deficient clones remain confined within the limits of their source epithelium, permitting survival of the host animal. Through interaction with the myosin II heavy chain subunit, Cher is likely to strengthen the cortical actomyosin network and reinforce mechanical tension within the invasive tumors. Accordingly, Cher is required for aberrant expression of genes downstream of the Hippo/Yorkie signaling in the tumor tissue. Our study identifies Cher as a new target of JNK signaling that links cytoskeleton dynamics to tumor progression.