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

Wei Zhang; Suat Peng Neo; Jayantha Gunaratne; Anders Poulsen; Liu Boping; Esther Hongqian Ong; Kanda Sangthongpitag; Vishal Pendharkar; Jeffrey Hill; Stephen Michael Cohen

doi:10.1016/j.cellsig.2014.12.010

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

Wei Zhang, Suat Peng Neo, Jayantha Gunaratne, Anders Poulsen, Liu Boping, Esther Hongqian Ong, Kanda Sangthongpitag, Vishal Pendharkar, Jeffrey Hill, Stephen Michael Cohen

Morphogenesis and Differentiation Program

23 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Cellular Signalling
Volume	27
Issue number	3
Pages (from-to)	436-42
Number of pages	7
ISSN	0898-6568
DOIs	https://doi.org/10.1016/j.cellsig.2014.12.010
Publication status	Published - 1 Mar 2015

Keywords

Amino Acid Substitution
Cell Line, Tumor
Endoplasmic Reticulum Stress
Forkhead Transcription Factors
HEK293 Cells
HeLa Cells
Hep G2 Cells
Humans
Nuclear Proteins
PTEN Phosphohydrolase
Phosphatidylinositol 3-Kinases
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-akt
Signal Transduction
Vault Ribonucleoprotein Particles
eIF-2 Kinase

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cellsig.2014.12.010Licence: CC BY-NC-ND

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@article{49dddbc8da0348fb8be6765eab073cf0,

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

abstract = "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.",

keywords = "Amino Acid Substitution, Cell Line, Tumor, Endoplasmic Reticulum Stress, Forkhead Transcription Factors, HEK293 Cells, HeLa Cells, Hep G2 Cells, Humans, Nuclear Proteins, PTEN Phosphohydrolase, Phosphatidylinositol 3-Kinases, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-akt, Signal Transduction, Vault Ribonucleoprotein Particles, eIF-2 Kinase",

author = "Wei Zhang and Neo, {Suat Peng} and Jayantha Gunaratne and Anders Poulsen and Liu Boping and Ong, {Esther Hongqian} and Kanda Sangthongpitag and Vishal Pendharkar and Jeffrey Hill and Cohen, {Stephen Michael}",

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year = "2015",

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doi = "10.1016/j.cellsig.2014.12.010",

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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

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 -

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

Abstract

Keywords

UN SDGs

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