JAK/STAT3-dependent activation of the RalGDS/Ral pathway in M1 mouse myeloid leukemia cells.
The Ras-related GTPase (Ral) is converted to the GTP-bound form by Ral guanine nucleotide dissociation stimulator (RalGDS), a putative effector protein of Ras. Recently, it was proven that Ral regulates c-Src activity and subsequent phosphorylation of its substrate, STAT3. Here, we show that STAT3 inversely regulates activation of Ral through induction of expression of RalGDS. To identify new leukemia inhibitory factor-induced genes, we have performed representational difference analysis using M1 mouse myeloid leukemia cells and cloned RalGDS. The expression of RalGDS and subsequent activation of RalA were clearly suppressed by a dominant negative form of STAT3 and a JAK inhibitor, JAB/SOCS1/SSI-1, indicating that RalGDS/RalA signaling requires the activation of the JAK/STAT3 pathway. An experiment using a Ras inhibitor demonstrated that full activation of RalA also requires activation of Ras. These results suggest a novel cross-talk between JAK/STAT3 and the Ras/RalGDS/Ral signaling pathways through gp130.
Senga
T
T
Department of Molecular Pathogenesis, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-Ku, Nagoya 466-8550, Japan.
Iwamoto
T
T
Kitamura
T
T
Miyake
Y
Y
Hamaguchi
M
M
D000209:Acute-Phase Proteins / Q000378:metabolism; D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism*; D020558:GTP Phosphohydrolases / Q000378:metabolism; D005786:Gene Expression Regulation; D007951:Leukemia, Myeloid; D008214:Lymphocytes / Q000166:cytology / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000502:physiology; D013154:Spleen / Q000276:immunology; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D020725:ral GTP-Binding Proteins / Q000378:metabolism*; D020726:ral Guanine Nucleotide Exchange Factor / Q000235:genetics* / Q000378:metabolism*
D000209:Acute-Phase Proteins; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D020726:ral Guanine Nucleotide Exchange Factor; D011505:Protein-Tyrosine Kinases; D016392:Proto-Oncogene Proteins pp60(c-src); D020558:GTP Phosphohydrolases; C118120:Rala protein, mouse; D020725:ral GTP-Binding Proteins