The small GTP-binding protein RhoA regulates c-jun by a ROCK-JNK signaling axis

Mol Cell. 2004 Apr 9;14(1):29-41. doi: 10.1016/s1097-2765(04)00153-4.

Abstract

RhoA regulates the actin cytoskeleton and the expression of genes associated with cell proliferation. This includes c-fos and c-jun, which are members of the AP1 family of transcription factors that play a key role in normal and aberrant cell growth. Whereas RhoA stimulates the c-fos SRE by a recently elucidated mechanism that is dependent on actin treadmilling, how RhoA regulates c-jun is still poorly understood. We found that RhoA stimulates c-jun expression through ROCK, but independently from the ability of ROCK to promote actin polymerization. Instead, we found that ROCK activates JNK, which then phosphorylates c-Jun and ATF2 when bound to the c-jun promoter. Thus, ROCK represents a point of signal divergence downstream from RhoA, as it promotes actin reorganization and the consequent expression from the c-fos SRE, while a parallel pathway connects ROCK to JNK, thereby stimulating c-jun expression. Ultimately, these pathways converge in the nucleus to regulate AP1 activity.

MeSH terms

  • Actin Depolymerizing Factors
  • Actins / metabolism
  • Activating Transcription Factor 2
  • Animals
  • Cell Line
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Cytoskeleton / metabolism
  • Enzyme Activation
  • Enzyme Inhibitors / metabolism
  • Gene Expression Regulation
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • JNK Mitogen-Activated Protein Kinases
  • Lim Kinases
  • Lysophospholipids / metabolism
  • Mice
  • Microfilament Proteins / metabolism
  • Mitogen-Activated Protein Kinases / metabolism*
  • NIH 3T3 Cells
  • Promoter Regions, Genetic
  • Protein Kinases / metabolism
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins c-jun / genetics
  • Proto-Oncogene Proteins c-jun / metabolism*
  • Signal Transduction / physiology*
  • Transcription Factors / metabolism
  • rho-Associated Kinases
  • rhoA GTP-Binding Protein / metabolism*

Substances

  • ATF2 protein, human
  • Actin Depolymerizing Factors
  • Actins
  • Activating Transcription Factor 2
  • Atf2 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • Enzyme Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • Lysophospholipids
  • Microfilament Proteins
  • Proto-Oncogene Proteins c-jun
  • Transcription Factors
  • Protein Kinases
  • LIMK1 protein, human
  • Lim Kinases
  • Limk1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • rho-Associated Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • rhoA GTP-Binding Protein
  • lysophosphatidic acid