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Generation of Null Mutants to Elucidate the Role of Bacterial Glycosyltransferases in Bacterial Motility
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ERK8 is a negative regulator of O-GalNAc glycosylation and cell migration

Joanne Chia1, Keit Min Tham, David James Gill

  • 1Institute of Molecular and Cell Biology, Singapore, Singapore.

Elife
|March 13, 2014
PubMed

Insights

Loss of ERK8 protein expression promotes cancer cell migration by enabling ER O-glycosylation. This pathway is hyperactivated in breast and lung carcinomas, suggesting ERK8 as a brake on cancer aggressiveness.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Endoplasmic reticulum (ER) O-glycosylation is regulated by the localization of GalNAc-Transferases (GalNAc-Ts).
  • Aberrant O-glycosylation is linked to increased cell migration and is a hallmark of many breast carcinomas.
  • The precise mechanisms controlling GalNAc-T localization and O-glycosylation in cancer remain largely unknown.

Purpose of the Study:

  • To identify signaling pathways regulating the sub-cellular localization of GalNAc-Ts.
  • To investigate the role of ERK8 in controlling ER O-glycosylation and cell motility.
  • To determine the clinical relevance of ERK8 expression in human carcinomas.

Main Methods:

  • Genome-wide RNA interference (RNAi) screen of 948 signaling genes coupled with high-content imaging.
  • Analysis of GalNAc-T and KDEL receptor localization.
  • Western blotting to assess protein expression levels.
  • Immunofluorescence microscopy to determine protein localization.

Main Results:

  • A screen identified 12 negative regulators of O-glycosylation, all affecting GalNAc-T localization.
  • ERK8, an atypical mitogen-activated protein kinase (MAPK), was identified as a key regulator.
  • ERK8 inhibition caused GalNAc-T relocalization via a COPI-dependent pathway, distinct from KDEL receptor trafficking.
  • ERK8 downregulation increased cell motility and was associated with reduced ERK8 expression and hyperactivated O-glycosylation in human breast and lung carcinomas.

Conclusions:

  • ERK8 acts as a constitutive brake on GalNAc-T relocalization and ER O-glycosylation.
  • Loss of ERK8 expression in cancer may drive increased cell migration and aggressiveness.
  • Targeting the ERK8-GalNAc-T axis could offer new therapeutic strategies for carcinomas.
Keywords:
COP-Icell migrationendoplasmic reticulumglycosylationgolgiretrograde traffic

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