Abstract
Autocrine motility factor/ phosphoglucose isomerase (AMF/PGI) promotes cell survival by the pAkt survival pathway. Its receptor, gp78/AMFR, is an E3 ubiquitin ligase implicated in endoplasmic reticulum (ER)-associated protein degradation. We demonstrate here that AMF/PGI also protects against thapsigargin (TG)- and tunicamycin (TUN)-induced ER stress and apoptosis. AMF/PGI protection against the ER stress response is receptor mediated as it is not observed in gp78/AMFR-knockdown HEK293 cells. However, AMF/PGI protection against the ER stress response by TG and TUN was mediated only partially through PI3K/Akt activation. AMF/PGI reduction of the elevation of cytosolic calcium in response to either TG or inositol 1,4,5-trisphosphate receptor activation with ATP was gp78/AMFR-dependent, independent of mitochondrial depolarization and not associated with changes in ER calcium content. These results implicate regulation of ER calcium release in AMF/PGI protection against ER stress and apoptosis. Indeed, sequestration of cytosolic calcium with BAPTA-AM limited the ER stress response. Importantly, elevation of cytosolic calcium upon treatment with the calcium ionophore ionomycin, while not inducing an ER stress response, did prevent AMF/PGI protection against ER stress. By regulating ER calcium release, AMF/PGI interaction with gp78/AMFR therefore protects against ER stress identifying novel roles for these cancer-associated proteins in promoting tumor cell survival.
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Accession codes
Abbreviations
- AMF/PGI:
-
autocrine motility factor/phosphoglucose isomerase
- AUC:
-
area under the curve
- Ca2+:
-
calcium
- [Ca2+]cyt:
-
cytosolic calcium concentration
- [Ca2+]m:
-
mitochondrial calcium concentration
- [Ca2+]ext:
-
extracellular calcium concentration
- [Ca2+]ER:
-
endoplasmic reticulum calcium concentration
- CCCP:
-
carbonyl cyanide m-chlorophenylhydrazone
- ER:
-
endoplasmic reticulum
- ERAD:
-
ER-associated protein degradation
- FRET:
-
fluorescence resonance energy transfer
- Gp78/AMFR:
-
glycoprotein 78/autocrine motility factor receptor
- IP3R:
-
1, 4, 5-trisphosphate receptors
- SERCA:
-
sarco/endoplasmic reticulum Ca2+-ATPase
- TG:
-
thapsigargin
- TUN:
-
tunicamycin
- UPR:
-
unfolded protein response
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Acknowledgements
We thank Dr Dan Luciani (UBC) for advice concerning the ER Ca2+ measurements. This study was supported by a grant from the Canadian Institutes for Health Research (CIHR MT-15132). LL is the recipient of a UBC Four Year Doctoral Fellowship; TA was supported by the Karl Heinz Frenzen Stiftung and JDJ was supported by a CIHR New Investigator Award.
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Fu, M., Li, L., Albrecht, T. et al. Autocrine motility factor/phosphoglucose isomerase regulates ER stress and cell death through control of ER calcium release. Cell Death Differ 18, 1057–1070 (2011). https://doi.org/10.1038/cdd.2010.181
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DOI: https://doi.org/10.1038/cdd.2010.181
