ERK8 is a negative regulator of O-GalNAc glycosylation and cell migration.
ERK8 is a negative regulator of O-GalNAc glycosylation and cell migration.
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ERK8是O-GalNAC糖基化和细胞迁移的负调节剂。
DOI：
10.7554/elife.01828
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发表时间：
2014-03-11
期刊：
影响因子：
7.7
通讯作者：
Bard FA
中科院分区：
文献类型：
--
作者：
Chia J;Tham KM;Gill DJ;Bard-Chapeau EA;Bard FA
内质网o糖基化可以通过高尔基体galnac转移酶的再定位来诱导。这一过程显著刺激细胞迁移，并在60%以上的乳腺癌中被组成性激活。这种激活是如何实现的尚不清楚。在这里，我们使用RNAi和成像技术筛选了948个信号基因。我们确定了12个o -糖基化负调节因子，它们都控制GalNAc-T亚细胞定位。ERK8是一种具有高基础激酶活性的非典型MAPK，是一种强烈的打击，部分定位于高尔基体。它的抑制作用诱导GalNAc-Ts的重新定位，但不诱导KDEL受体的重新定位，这表明存在两种独立的copi依赖途径。反过来，ERK8下调激活细胞运动。在人乳腺癌和肺癌中，ERK8表达降低，而ER o糖基化起始过度激活。总之，ERK8作为GalNAc-T重定位的组成性制动器出现，其表达的丧失可以通过增加细胞运动性来驱动癌症的侵袭性。一个人能够从癌症中康复的可能性取决于：癌症在体内的位置，疾病被发现的速度和开始治疗的速度。癌症从原来的位置扩散到身体的另一部分，治疗起来尤其具有挑战性，每年绝大多数癌症死亡都是由癌症引起的。我们仍然需要能够识别和根除癌细胞，同时不触及附近的健康细胞的治疗方法，因此人们已经进行了大量的研究，以确定健康细胞和癌细胞之间的关键区别。几十年来，研究人员已经意识到，癌细胞比健康细胞在细胞表面有更多被修饰糖包裹的蛋白质。这是由酶引起的，这些酶将这些糖添加到蛋白质中，从细胞内的一个位置，即高尔基体，转移到另一个位置，即内质网。众所周知，这些特殊的“糖衣”蛋白会促使癌细胞迁移并侵入新的组织，但调控这些糖分子添加到蛋白质中的机制仍然知之甚少。现在，Chia等人已经发现了12种调节这一过程的分子，包括一种在高尔基体中发现的名为ERK8的酶。ERK8被证明可以阻止糖添加酶从高尔基体转移到内质网，从而限制糖包被蛋白的产生，而糖包被蛋白有助于癌细胞在体内扩散。Chia等人的研究确定了12种新疗法的潜在靶点，旨在防止癌症的扩散，最终可能有助于提高某些癌症患者康复的机会。DOI: http://dx.doi.org/10.7554/eLife.01828.002
ER O-glycosylation can be induced through relocalisation GalNAc-Transferases from the Golgi. This process markedly stimulates cell migration and is constitutively activated in more than 60% of breast carcinomas. How this activation is achieved remains unclear. Here, we screened 948 signalling genes using RNAi and imaging. We identified 12 negative regulators of O-glycosylation that all control GalNAc-T sub-cellular localisation. ERK8, an atypical MAPK with high basal kinase activity, is a strong hit and is partially localised at the Golgi. Its inhibition induces the relocation of GalNAc-Ts, but not of KDEL receptors, revealing the existence of two separate COPI-dependent pathways. ERK8 down-regulation, in turn, activates cell motility. In human breast and lung carcinomas, ERK8 expression is reduced while ER O-glycosylation initiation is hyperactivated. In sum, ERK8 appears as a constitutive brake on GalNAc-T relocalisation, and the loss of its expression could drive cancer aggressivity through increased cell motility. DOI: http://dx.doi.org/10.7554/eLife.01828.001 The likelihood of an individual being able to recover from cancer depends on: where the cancer is within the body, how quickly the disease is detected and how quickly treatment is started. Cancers that have spread from their original location to another part of the body are particular challenging to treat, and cause the vast majority of cancer deaths every year. Treatments that can recognize and eradicate cancer cells, while leaving nearby healthy cells untouched, are still needed—and so there has been a lot of research into identifying the key differences between healthy cells and cancer cells. For several decades, researchers have been aware that cancer cells have more proteins coated with modified sugars on their cell surfaces than healthy cells. This is caused by the enzymes that add these sugars to the proteins relocating from one location within the cell, the Golgi apparatus, to another, called the endoplasmic reticulum. These specific ‘sugar-coated’ proteins are known to encourage cancer cells to migrate and invade new tissues, but the mechanisms that regulate the addition of these sugar molecules to proteins remains poorly understood. Now Chia et al. have discovered 12 molecules that regulate this process, including an enzyme called ERK8 that is found at the Golgi apparatus. ERK8 is shown to prevent the relocation of the sugar-adding enzymes from the Golgi to the endoplasmic reticulum, thereby restricting the production of sugar-coated proteins that help the cancer cells to spread within the body. By identifying 12 potential targets for new therapeutics aimed at preventing the spread of cancer, the work of Chia et al. could ultimately help to improve the chances of patients recovering from certain cancers. DOI: http://dx.doi.org/10.7554/eLife.01828.002