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Cooperation between Syk and Rac1 leads to synergistic JNK activation in T lymphocytes
1Department of Pharmacology, University of California, San Diego, La Jolla 92093-0636, USA.
Abstract:
The MAP kinase (MAPK) JNK but not ERK is synergistically activated during costimulation of T cells. We examined how protein tyrosine kinases (PTKs) and GTPases differentially regulate JNK and ERK in T cells. While PTKs are not selective, small GTPases display distinct MAPK-activating functions. Whereas Ras activates ERK, Rac activates JNK. Rac cooperates with a Syk-generated signal to enhance JNK activation and appears to be at a nodal point for pathways emanating from CD28, calcineurin, and protein kinase C. AP-1- and NF-AT-dependent reporters are stimulated by Rac and Syk and are dependent on JNK. Unlike Syk, the PTK Lck activates JNK but does not cooperate with Rac, resulting in weak AP-1 and NF-AT activation. Therefore, signals generated by PTKs are functionally distinct and need to be integrated to induce transcriptional responses.
Insights
Small GTPases like Rac selectively activate JNK, while Ras activates ERK in T cells. Rac and Syk cooperate for JNK activation, influencing T cell responses.
Area of Science:
- Immunology
- Cell Signaling
- Molecular Biology
Background:
- T cell costimulation involves complex signaling pathways regulating T cell activation.
- Mitogen-activated protein kinases (MAPKs), including JNK and ERK, are crucial in T cell responses.
- Protein tyrosine kinases (PTKs) and small GTPases are key regulators of intracellular signaling.
Purpose of the Study:
- To investigate the differential regulation of JNK and ERK by PTKs and GTPases in T cells.
- To elucidate the role of Rac and Syk in JNK activation and downstream transcriptional responses.
Main Methods:
- Analysis of MAPK activation in T cells.
- Investigation of GTPase and PTK functions in T cell signaling.
- Use of reporter assays to measure transcriptional activity (AP-1 and NF-AT).
Main Results:
- Rac specifically activates JNK, whereas Ras activates ERK in T cells.
- Rac cooperates with Syk to enhance JNK activation, impacting CD28, calcineurin, and PKC pathways.
- Lck activates JNK but does not cooperate with Rac, leading to reduced AP-1 and NF-AT activation compared to Syk.
Conclusions:
- Small GTPases exhibit distinct roles in regulating JNK and ERK pathways.
- Syk-mediated signaling cooperates with Rac for robust JNK activation and transcriptional responses.
- PTK signals are functionally diverse and require integration for effective T cell transcriptional outcomes.