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Autocrine motility factor/phosphoglucose isomerase regulates ER stress and cell death through control of ER calcium

M Fu1, L Li, T Albrecht

  • 1Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.

Cell Death and Differentiation
|January 22, 2011
PubMed

Insights

Autocrine motility factor/phosphoglucose isomerase (AMF/PGI) protects cells from ER stress and apoptosis. This involves regulating calcium release via its receptor, gp78/AMFR, highlighting new roles in tumor cell survival.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Autocrine motility factor/phosphoglucose isomerase (AMF/PGI) is known to promote cell survival through the pAkt pathway.
  • Its receptor, gp78/AMFR, functions as an E3 ubiquitin ligase involved in endoplasmic reticulum (ER)-associated protein degradation.

Purpose of the Study:

  • To investigate the role of AMF/PGI and its receptor gp78/AMFR in protecting against ER stress and apoptosis.
  • To elucidate the mechanisms underlying AMF/PGI-mediated protection against ER stress, particularly concerning calcium signaling.

Main Methods:

  • Utilized HEK293 cells with and without gp78/AMFR knockdown.
  • Induced ER stress using thapsigargin (TG) and tunicamycin (TUN).
  • Assessed cell survival, apoptosis, cytosolic calcium levels, ER calcium content, and mitochondrial membrane potential.

Main Results:

  • AMF/PGI conferred protection against TG- and TUN-induced ER stress and apoptosis in a receptor-dependent manner.
  • Protection was only partially mediated by PI3K/Akt activation.
  • AMF/PGI reduced elevated cytosolic calcium levels in a gp78/AMFR-dependent manner, independent of mitochondrial depolarization and ER calcium content changes.
  • Sequestration of cytosolic calcium limited the ER stress response, while elevated cytosolic calcium prevented AMF/PGI protection.

Conclusions:

  • AMF/PGI, through interaction with gp78/AMFR, protects against ER stress and apoptosis by regulating ER calcium release.
  • These findings identify novel roles for AMF/PGI and gp78/AMFR in promoting tumor cell survival.
  • The study implicates calcium signaling regulation as a key mechanism in AMF/PGI's protective effects against ER stress.

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