ERK and the F-box protein betaTRCP target STAT1 for degradation

J Biol Chem. 2008 Jun 6;283(23):16077-83. doi: 10.1074/jbc.M800384200. Epub 2008 Mar 31.


The transcription factor STAT1 has roles in development, homeostasis, cellular differentiation, and apoptosis and has been postulated to function as a tumor suppressor. STAT1 is activated by tyrosine or serine phosphorylation in response to specific cytokines or following a variety of stress-induced stimuli. STAT1 activity is carefully regulated to prevent sustained STAT1-mediated transcription, although the molecular mechanisms involved in the modulation of STAT1 stability are poorly understood. Here we show that activated STAT1 is degraded at the proteasome by a mechanism involving the F-box E3 ligase, SCF(betaTRCP). Active p42/p44 MAPK-ERK phosphorylates STAT1 on serine 727 and targets it for proteasomal degradation. SCF(betaTRCP) binds wild-type STAT1 but not the nonphosphorylatable mutant STAT1(S727A). Moreover, silencing betaTRCP expression or pharmacological inhibition of ERK activity stabilized STAT1 expression. These data suggest that constitutively active ERK may inappropriately degrade STAT1, with loss of its pro-apoptotic and tumor suppressor functions.

Publication types

  • Research Support, Non-U.S. Gov't
  • Retracted Publication

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Cell Differentiation / physiology
  • Cell Line
  • Cytokines / genetics
  • Cytokines / metabolism
  • Homeostasis / physiology
  • Mice
  • Mitogen-Activated Protein Kinase 1 / genetics
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Phosphorylation
  • Proteasome Endopeptidase Complex / genetics
  • Proteasome Endopeptidase Complex / metabolism
  • STAT1 Transcription Factor / genetics
  • STAT1 Transcription Factor / metabolism*
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism
  • beta-Transducin Repeat-Containing Proteins / genetics
  • beta-Transducin Repeat-Containing Proteins / metabolism*


  • Cytokines
  • STAT1 Transcription Factor
  • Stat1 protein, mouse
  • Tumor Suppressor Proteins
  • beta-Transducin Repeat-Containing Proteins
  • Ubiquitin-Protein Ligases
  • Mitogen-Activated Protein Kinase 1
  • Proteasome Endopeptidase Complex