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

TY - JOUR

T1 - Feedback regulation on PTEN/AKT pathway by the ER stress kinase PERK mediated by interaction with the Vault complex

AU - Zhang, Wei

AU - Neo, Suat Peng

AU - Gunaratne, Jayantha

AU - Poulsen, Anders

AU - Boping, Liu

AU - Ong, Esther Hongqian

AU - Sangthongpitag, Kanda

AU - Pendharkar, Vishal

AU - Hill, Jeffrey

AU - Cohen, Stephen Michael

N1 - Copyright © 2014. Published by Elsevier Inc.

PY - 2015/3/1

Y1 - 2015/3/1

N2 - 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.

AB - 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.

KW - Amino Acid Substitution

KW - Cell Line, Tumor

KW - Endoplasmic Reticulum Stress

KW - Forkhead Transcription Factors

KW - HEK293 Cells

KW - HeLa Cells

KW - Hep G2 Cells

KW - Humans

KW - Nuclear Proteins

KW - PTEN Phosphohydrolase

KW - Phosphatidylinositol 3-Kinases

KW - Protein Kinase Inhibitors

KW - Proto-Oncogene Proteins c-akt

KW - Signal Transduction

KW - Vault Ribonucleoprotein Particles

KW - eIF-2 Kinase

U2 - 10.1016/j.cellsig.2014.12.010

DO - 10.1016/j.cellsig.2014.12.010

M3 - Journal article

C2 - 25530215

SN - 0898-6568

VL - 27

SP - 436

EP - 442

JO - Cellular Signalling

JF - Cellular Signalling

IS - 3

ER -