ERK8 is a negative regulator of O-GalNAc glycosylation and cell migration

  • Chia J
  • Tham K
  • Gill D
  • et al.
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Abstract

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.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.

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Chia, J., Tham, K. M., Gill, D. J., Bard-Chapeau, E. A., & Bard, F. A. (2014). ERK8 is a negative regulator of O-GalNAc glycosylation and cell migration. ELife, 3. https://doi.org/10.7554/elife.01828

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