Feedback regulation on PTEN/AKT pathway by the ER stress kinase PERK mediated by interaction with the Vault complex

• Published in: Cellular signalling 2015-03, Vol.27 (3), p.436-442
• Main Authors: Zhang, Wei, Neo, Suat Peng, Gunaratne, Jayantha, Poulsen, Anders, Boping, Liu, Ong, Esther Hongqian, Sangthongpitag, Kanda, Pendharkar, Vishal, Hill, Jeffrey, Cohen, Stephen M.
• Format: Article
• Language: English
• Subjects: Amino Acid Substitution; Cell Line, Tumor; eIF-2 Kinase - antagonists & inhibitors; eIF-2 Kinase - genetics; eIF-2 Kinase - metabolism; Endoplasmic Reticulum Stress - drug effects; ER stress; Forkhead Box Protein O1; Forkhead Transcription Factors - metabolism; HEK293 Cells; HeLa Cells; Hep G2 Cells; Humans; MVP; Nuclear Proteins - metabolism; PERK inhibitors; Phosphatidylinositol 3-Kinases - metabolism; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-akt - metabolism; PTEN; PTEN Phosphohydrolase - metabolism; Signal Transduction - drug effects; Vault Ribonucleoprotein Particles - chemistry; Vault Ribonucleoprotein Particles - metabolism; Vaults
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2014.12.010

The high proliferation rate of cancer cells, together with environmental factors such as hypoxia and nutrient deprivation can cause Endoplasmic Reticulum (ER) stress. The protein kinase PERK is an essential mediator in one of the three ER stress response pathways. Genetic and pharmacological inhibition of PERK has been reported to limit tumor growth in xenograft models. Here we provide evidence that inactive PERK interacts with the nuclear pore-associated Vault complex protein and that this compromises Vault-mediated nuclear transport of PTEN. Pharmacological inhibition of PERK under ER stress results is abnormal sequestration of the Vault complex, leading to increased cytoplasmic PTEN activity and lower AKT activation. As the PI3K/PTEN/AKT pathway is crucial for many aspects of cell growth and survival, this unexpected effect of PERK inhibitors on AKT activity may have implications for their potential use as therapeutic agents. •We report an unexpected crosstalk between the ER stress and PI3K pathways.•Inhibition of PERK kinase leads to abberant interaction with the Vault complex.•This results from pharmacological inhibition of PERK or with a kinase-inactive form.•PERK–vault interaction changes PTEN subcellular location, affecting AKT activity.•This finding has implications for the use of PERK inhibitors as therapeutic agents.