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.
authors.affiliation: Institute of Molecular and Cell Biology, 61 Biopolis Drive, Singapore 138673, Singapore.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Institute of Molecular and Cell Biology, 61 Biopolis Drive, Singapore 138673, Singapore.
authors.forename: Suat Peng
authors.initials: SP
authors.lastname: Neo
authors.affiliation: Institute of Molecular and Cell Biology, 61 Biopolis Drive, Singapore 138673, Singapore.
authors.forename: Jayantha
authors.initials: J
authors.lastname: Gunaratne
authors.affiliation: Experimental Therapeutics Center, 31 Biopolis Way, Singapore 138669, Singapore.
authors.forename: Anders
authors.initials: A
authors.lastname: Poulsen
authors.affiliation: Experimental Therapeutics Center, 31 Biopolis Way, Singapore 138669, Singapore.
authors.forename: Liu
authors.initials: L
authors.lastname: Boping
authors.affiliation: Experimental Therapeutics Center, 31 Biopolis Way, Singapore 138669, Singapore.
authors.forename: Esther Hongqian
authors.initials: EH
authors.lastname: Ong
authors.affiliation: Experimental Therapeutics Center, 31 Biopolis Way, Singapore 138669, Singapore.
authors.forename: Kanda
authors.initials: K
authors.lastname: Sangthongpitag
authors.affiliation: Experimental Therapeutics Center, 31 Biopolis Way, Singapore 138669, Singapore.
authors.forename: Vishal
authors.initials: V
authors.lastname: Pendharkar
authors.affiliation: Experimental Therapeutics Center, 31 Biopolis Way, Singapore 138669, Singapore.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Hill
authors.affiliation: Institute of Molecular and Cell Biology, 61 Biopolis Drive, Singapore 138673, Singapore; Department of Biological Sciences, National University of Singapore, 117543, Singapore. Electronic address: scohen@imcb.a-star.edu.sg.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Cohen
mesh_terms: D019943:Amino Acid Substitution; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020394:Vault Ribonucleoprotein Particles / Q000737:chemistry / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000099187:Major Vault Protein
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D009687:Nuclear Proteins; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D020394:Vault Ribonucleoprotein Particles; D019892:eIF-2 Kinase; D000099187:Major Vault Protein; C085126:FOXO1 protein, human; C118687:PARP4 protein, human; C494929:PTEN protein, human
keywords: ER stress; MVP; PERK inhibitors; PTEN; Vaults