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JAK/STAT3-dependent activation of the RalGDS/Ral pathway in M1 mouse myeloid leukemia cells
T Senga1, T Iwamoto, T Kitamura
1Department of Molecular Pathogenesis, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-Ku, Nagoya 466-8550, Japan.
Abstract:
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.
Insights
STAT3 regulates Ral signaling by inducing RalGDS expression, revealing a cross-talk between JAK/STAT3 and Ras/Ral pathways. This interaction is crucial for RalA activation, involving Ras and gp130.
Area of Science:
- Molecular Biology
- Cell Signaling
- Cancer Research
Background:
- Ras-related GTPase (Ral) activation is mediated by Ral guanine nucleotide dissociation stimulator (RalGDS).
- Ral signaling influences c-Src activity and STAT3 phosphorylation.
- STAT3 is a key transcription factor in cellular signaling pathways.
Purpose of the Study:
- To investigate the regulatory relationship between STAT3 and Ral signaling.
- To identify leukemia inhibitory factor-induced genes.
- To elucidate the cross-talk between JAK/STAT3 and Ras/RalGDS/Ral pathways.
Main Methods:
- Representational difference analysis in M1 mouse myeloid leukemia cells.
- Cloning of RalGDS.
- Use of dominant-negative STAT3 and JAK inhibitors (JAB/SOCS1/SSI-1).
- Ras inhibitor experiments.
Main Results:
- STAT3 was found to inversely regulate Ral activation by inducing RalGDS expression.
- RalGDS expression and RalA activation were suppressed by dominant-negative STAT3 and JAK inhibitors.
- Full RalA activation requires both Ras activation and the JAK/STAT3 pathway.
Conclusions:
- STAT3 positively regulates RalGDS expression, linking JAK/STAT3 and Ras/Ral signaling.
- A novel cross-talk mechanism between JAK/STAT3 and Ras/RalGDS/Ral pathways, mediated by gp130, was identified.
- This cross-talk is essential for RalA activation and may have implications in myeloid leukemia.