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Human Molecular Genetics Advance Access originally published online on July 29, 2008
Human Molecular Genetics 2008 17(20):3254-3262; doi:10.1093/hmg/ddn221
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Polycystin-2 down-regulates cell proliferation via promoting PERK-dependent phosphorylation of eIF2{alpha}

Genqing Liang{dagger}, JungWoo Yang{dagger}, Zuocheng Wang, Qiang Li, Yan Tang and Xing-Zhen Chen*

Membrane Protein Research Group, Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada T6G 2H7

* To whom correspondence should be addressed. Tel: +1 7804922294; Fax: +1 7804928915; Email: xzchen{at}ualberta.ca

Received June 12, 2008; Accepted July 25, 2008

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the formation of renal, hepatic and pancreatic cysts and by non-cystic manifestations such as abnormal vasculature and embryo left–right asymmetry development. Polycystin-2 (PC2), in which mutations account for 10–15% of ADPKD, was previously shown to down-regulate cell proliferation, but the underlying mechanism was not elucidated. Here, we demonstrate that PC2, but not pathogenic mutants E837X and R872X, represses cell proliferation through promoting the phosphorylation of eukaryotic translation initiation factor eIF2{alpha} by pancreatic ER-resident eIF2{alpha} kinase (PERK). ER stress is known to enhance eIF2{alpha} phosphorylation through up-regulating PERK kinase activity (assessed by phosphorylated PERK). During ER stress, PC2 knockdown also repressed eIF2{alpha} phosphorylation but did not alter PERK phosphorylation, indicating that PC2 facilitates the eIF2{alpha} phosphorylation by PERK. PC2 was found to be in the same complex as PERK and eIF2{alpha}. Together, we demonstrate that PC2 negatively controls cell growth by promoting PERK-mediated eIF2{alpha} phosphorylation, presumably through physical interaction, which may underlie a pathogenesis mechanism of ADPKD and indicates that PC2 is an important regulator of the translation machinery.

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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