The small-GTPase RalA activates transcription of the urokinase plasminogen activator receptor (uPAR) gene via an AP1-dependent mechanism

Oncogene. 2001 Apr 5;20(15):1816-24. doi: 10.1038/sj.onc.1204260.


The urokinase plasminogen activator receptor (uPAR) focuses extracellular protease activity to the cell surface, modulates cell adhesion and activates intracellular signal transduction pathways. In a range of cancers uPAR expression often has a negative correlation with prognosis. Here we show that uPAR transcription is stimulated by V12 H-Ras, the effector loop mutant V12 H-Ras G37 and constitutively-active RalA 72L. RalA-dependent transcription required the presence of the ATF2-like AP1-site at -70 bp and the c-Jun binding motif at -184 bp in the uPAR promoter. Consistent with this, both Gal4-c-Jun- and Gal4-ATF2-fusion proteins were activated by RalA signalling through phosphorylation of their activation domains at Ser63 and Ser73 of c-Jun or Thr69 and Thr71 of ATF2. A transdominant inhibitory mutant of c-Jun N-terminal kinase (JNK) failed to inhibit uPAR transcription demonstrating that JNK activation is not a prerequisite for RalA-dependent uPAR transcription. A dominant negative inhibitor of c-Src effectively inhibited RalA-dependent uPAR transcription identifying it as a downstream effector in the RalA signalling pathway. These data provide evidence for the existence of a novel signalling pathway that links RalA to the activation of uPAR transcription via a c-Src intermediate and activation of AP1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 2
  • Base Sequence
  • CSK Tyrosine-Protein Kinase
  • Cell Line
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • GTP Phosphohydrolases / physiology*
  • Genes, ras
  • Humans
  • Molecular Sequence Data
  • Promoter Regions, Genetic
  • Protein-Tyrosine Kinases / physiology
  • Proto-Oncogene Proteins c-jun / metabolism
  • Receptors, Cell Surface / genetics*
  • Receptors, Urokinase Plasminogen Activator
  • Response Elements
  • Trans-Activators / physiology*
  • Transcription Factor AP-1 / physiology*
  • Transcription Factors / metabolism
  • ral GTP-Binding Proteins*
  • src-Family Kinases


  • ATF2 protein, human
  • Activating Transcription Factor 2
  • Cyclic AMP Response Element-Binding Protein
  • PLAUR protein, human
  • Proto-Oncogene Proteins c-jun
  • Receptors, Cell Surface
  • Receptors, Urokinase Plasminogen Activator
  • Trans-Activators
  • Transcription Factor AP-1
  • Transcription Factors
  • Protein-Tyrosine Kinases
  • CSK Tyrosine-Protein Kinase
  • src-Family Kinases
  • CSK protein, human
  • GTP Phosphohydrolases
  • RALA protein, human
  • ral GTP-Binding Proteins