The small GTPase RALA controls c-Jun N-terminal kinase-mediated FOXO activation by regulation of a JIP1 scaffold complex

J Biol Chem. 2013 Jul 26;288(30):21729-41. doi: 10.1074/jbc.M113.463885. Epub 2013 Jun 14.


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.

Keywords: C. elegans; MAP Kinases (MAPKs); Reactive Oxygen Species (ROS); Scaffold Proteins; Signal Transduction; Small GTPases; Transcription Factors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Blotting, Western
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / metabolism
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism
  • Cell Cycle Proteins
  • Cell Nucleus / metabolism
  • Enzyme Activation
  • Forkhead Transcription Factors
  • HEK293 Cells
  • Humans
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism
  • Mice
  • Mitogen-Activated Protein Kinase 8 / genetics
  • Mitogen-Activated Protein Kinase 8 / metabolism*
  • Mutation
  • NIH 3T3 Cells
  • RNA Interference
  • Reactive Oxygen Species / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • ral GTP-Binding Proteins / genetics
  • ral GTP-Binding Proteins / metabolism*


  • Adaptor Proteins, Signal Transducing
  • Caenorhabditis elegans Proteins
  • Cell Cycle Proteins
  • FOXO4 protein, human
  • Forkhead Transcription Factors
  • MAPK8IP1 protein, human
  • RLF protein, human
  • Reactive Oxygen Species
  • Transcription Factors
  • Mitogen-Activated Protein Kinase 8
  • MAP Kinase Kinase Kinases
  • RALA protein, human
  • ral GTP-Binding Proteins