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p21ras and calcineurin synergize to regulate the nuclear factor of activated T cells
M Woodrow1, N A Clipstone, D Cantrell
1Lymphocyte Activation Laboratory, Imperial Cancer Research Fund, London, England.
Abstract:
In T lymphocytes, triggering of the T cell receptor (TCR) induces several signaling cascades which ultimately synergize to induce the activity of the nuclear factor of activated T cells (NFAT), a DNA binding complex critical to the inducibility and T cell specificity of the T cell growth factor interleukin 2. One immediate consequence of T cell activation via the TCR is an increase in cytosolic calcium. Calcium signals are important for NFAT induction, and recent studies have identified calcineurin, a calcium-calmodulin dependent serine-threonine phosphatase, as a prominent component of the calcium signaling pathway in T cells. A second important molecule in TCR signal transduction is the guanine nucleotide binding protein, p21ras, which is coupled to the TCR by a protein tyrosine kinase dependent mechanism. The experiments presented here show that expression by transfection of mutationally activated calcineurin or activated p21ras alone is insufficient for NFAT transactivation. However, coexpression of the activated calcineurin with activated p21ras could mimic TCR signals in NFAT induction. These data identify calcineurin and p21ras as cooperative partners in T cell activation.
Insights
T cell receptor (TCR) activation involves calcium signaling via calcineurin and p21ras pathways. Co-activating both calcineurin and p21ras mimics TCR signals, leading to nuclear factor of activated T cells (NFAT) induction.
Area of Science:
- Immunology
- Molecular Biology
- Cell Signaling
Background:
- T cell receptor (TCR) activation initiates signaling cascades crucial for T cell function, including interleukin 2 production.
- Nuclear factor of activated T cells (NFAT) is a key transcription factor regulated by TCR signaling, controlling T cell inducibility and specificity.
- Calcium influx and the guanine nucleotide binding protein p21ras are critical components of TCR-mediated signal transduction.
Purpose of the Study:
- To investigate the roles of calcineurin and p21ras in T cell activation and NFAT induction.
- To determine if calcineurin and p21ras act independently or cooperatively in TCR signaling.
Main Methods:
- Utilized transfection experiments to express activated forms of calcineurin and p21ras in T cells.
- Assessed the impact of expressing activated calcineurin and/or p21ras on NFAT transactivation.
Main Results:
- Expression of activated calcineurin or activated p21ras alone was insufficient to induce NFAT transactivation.
- Co-expression of activated calcineurin and activated p21ras successfully mimicked TCR signals, leading to NFAT induction.
Conclusions:
- Calcineurin and p21ras function as cooperative partners in T cell activation pathways.
- These findings elucidate a key mechanism of TCR signaling convergence on NFAT activation.