Cytoplasmic c-Fos induced by the YXXQ-derived STAT3 signal requires the co-operative MEK/ERK signal for its nuclear translocation

Genes Cells. 2004 Mar;9(3):233-42. doi: 10.1111/j.1356-9597.2004.00715.x.


A STAT3 (signal transducer and activator of transcription 3)- and a MEK/Erk-mediated signal can be activated by cytokines, including IL-6 (interleukin-6), PDGF, and EGF. Recently, STAT3 and an ERK-signal were shown to co-operatively activate the c-fos gene. Activation of a truncated form of the IL-6 receptor subunit, gp130, that had only one YXXQ motif, induced both c-Fos and JunB in NIH3T3 cells through STAT3 without an apparent increase in the AP-1 (activator protein-1) activity. In contrast, concomitant stimulation of the STAT3 signal and a MEK/Erk-signal markedly increased AP-1 activity with enhanced c-Fos expression. Surprisingly, the c-Fos induced by the YXXQ-signal alone was localized to the cytoplasm, from which it translocated into the nucleus following TPA (12-O-tetradecanoyl-phorbol 13-acetate) treatment in a MEK/Erk-dependent manner. c-Fos that was expressed from a constitutive promoter localized to the nucleus and did not move into the cytoplasm in response to the YXXQ-signal. Rather, the YXXQ-signal was required during c-Fos production for it to be retained in the cytoplasm. Thus, the YXXQ-signal induces c-Fos expression through STAT3 and anchors the new c-Fos in the cytoplasm. In addition, the YXXQ-signal and an Erk signal co-operatively cause c-Fos activation in the nucleus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Amino Acid Motifs
  • Animals
  • Antigens, CD / chemistry*
  • Antigens, CD / metabolism
  • Cell Line
  • Cell Nucleus / metabolism*
  • Cytokine Receptor gp130
  • Cytoplasm / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Electrophoretic Mobility Shift Assay
  • Gene Expression Regulation
  • Granulocyte Colony-Stimulating Factor / metabolism
  • MAP Kinase Signaling System
  • Membrane Glycoproteins / chemistry*
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mitogen-Activated Protein Kinase Kinases / genetics
  • Mitogen-Activated Protein Kinase Kinases / metabolism*
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism*
  • Protein Transport
  • Proto-Oncogene Proteins c-fos / biosynthesis
  • Proto-Oncogene Proteins c-fos / genetics
  • Proto-Oncogene Proteins c-fos / metabolism*
  • Proto-Oncogene Proteins c-jun / genetics
  • Proto-Oncogene Proteins c-jun / metabolism
  • STAT3 Transcription Factor
  • Signal Transduction
  • Tissue Polypeptide Antigen / metabolism
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcription Factor AP-1 / genetics
  • Transcription Factor AP-1 / metabolism


  • Antigens, CD
  • DNA-Binding Proteins
  • Il6st protein, mouse
  • Membrane Glycoproteins
  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins c-jun
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Tissue Polypeptide Antigen
  • Trans-Activators
  • Transcription Factor AP-1
  • Cytokine Receptor gp130
  • Granulocyte Colony-Stimulating Factor
  • Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase Kinases