title: The small GTPase RALA controls c-Jun N-terminal kinase-mediated FOXO activation by regulation of a JIP1 scaffold complex.
abstract: FOXO (forkhead box O) transcription factors are tumor suppressors and increase the life spans of model organisms. Cellular stress, in particular oxidative stress caused by an increase in levels of reactive oxygen species (ROS), activates FOXOs through JNK-mediated phosphorylation. Importantly, JNK regulation of FOXO is evolutionarily conserved. Here we identified the pathway that mediates ROS-induced JNK-dependent FOXO regulation. Following increased ROS, RALA is activated by the exchange factor RLF (RalGDS-like factor), which is in complex with JIP1 (C-Jun-amino-terminal-interacting protein 1) and JNK. Active RALA consequently regulates assembly and activation of MLK3, MKK4, and JNK onto the JIP1 scaffold. Furthermore, regulation of FOXO by RALA and JIP1 is conserved in C. elegans, where both ral-1 and jip-1 depletion impairs heat shock-induced nuclear translocation of the FOXO orthologue DAF16.
authors.affiliation: Molecular Cancer Research, University Medical Center Utrecht, Utrecht, 3584 CG, The Netherlands.
authors.forename: Maaike C W
authors.initials: MC
authors.lastname: van den Berg
authors.forename: Inkie J A
authors.initials: IJ
authors.lastname: van Gogh
authors.forename: Alida M M
authors.initials: AM
authors.lastname: Smits
authors.forename: Miranda
authors.initials: M
authors.lastname: van Triest
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Dansen
authors.forename: Marieke
authors.initials: M
authors.lastname: Visscher
authors.forename: Paulien E
authors.initials: PE
authors.lastname: Polderman
authors.forename: Marjolein J
authors.initials: MJ
authors.lastname: Vliem
authors.forename: Holger
authors.initials: H
authors.lastname: Rehmann
authors.forename: Boudewijn M T
authors.initials: BM
authors.lastname: Burgering
mesh_terms: D021581:Active Transport, Cell Nucleus; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins; D002467:Cell Nucleus / Q000378:metabolism; D004789:Enzyme Activation; D051858:Forkhead Transcription Factors; D057809:HEK293 Cells; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D041681:NIH 3T3 Cells; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D020725:ral GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D029742:Caenorhabditis elegans Proteins; D018797:Cell Cycle Proteins; C108803:FOXO4 protein, human; D051858:Forkhead Transcription Factors; C490666:MAPK8IP1 protein, human; C097542:RLF protein, human; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D048055:Mitogen-Activated Protein Kinase 8; D020930:MAP Kinase Kinase Kinases; C492198:RALA protein, human; D020725:ral GTP-Binding Proteins
keywords: C. elegans; MAP Kinases (MAPKs); Reactive Oxygen Species (ROS); Scaffold Proteins; Signal Transduction; Small GTPases; Transcription Factors