Trends in Immunology
ReviewRas and extracellular signal-regulated kinase signaling in thymocytes and T cells
Highlights
► RasGEF expression is developmentally regulated in thymocytes. ► Thymocyte negative selection requires either Sos1 or RasGRP1, but is ERK-independent. ► Ras-dependent and Ras-independent pathways signal to ERK in peripheral T cells. ► Bam32−PLC-γ1−PAK1 complexes activate ERK independently of LAT and Ras.
Section snippets
TCR signal transduction to Ras
Receptor-stimulated signal transduction through the small G protein Ras to the Raf−MEK−ERK kinase cascade is essential to multiple developmental and pathologic systems. As a result of this, defining and targeting the signaling proteins that underlie Ras and ERK activation has enormous therapeutic potential 1, 2, 3, 4. In T cells, signal transduction from two related receptors, the pre-TCR and TCR, to the small G protein Ras and the downstream Raf−MEK−ERK kinase cascade is absolutely required
RAS activation during thymocyte development
Genetic studies of thymocyte development have shown that signal transduction from the pre-TCR and TCR, through the adapters LAT and SLP76, to the small G protein Ras and downstream mitogen activated protein kinase (MAPK) cascades is required during several stages 7, 11, 13, 14, 30, 31. For a brief review of thymocyte development, see Box 1. However, a mechanistic understanding of Ras activation during thymocyte development has been elusive. Recently, two models have been proposed to explain how
Toward an integrated model of RasGEF signaling during thymocyte development
Neither of the described models sufficiently explains Ras activation at both the pre-TCR and TCR developmental checkpoints. Mice that are deficient for Sos1 specifically in the T cell lineage [Sos1(T)−/−] contain some cells that develop beyond the DN3 stage [26], suggesting a role for other RasGEFs in β selection. Rasgrp1−/− mice, which in theory are unable to initiate RasGRP1−Ras−Sos−Ras signaling, show intact negative selection [34]. Furthermore, transgenic expression of a dominant-negative
ERK activation during thymocyte development
Combined deletion of ERK1 and ERK2 shows that Raf−MEK−ERK signaling is required for β selection downstream of the pre-TCR and for positive selection downstream of the TCR 7, 9. Furthermore, the intensity, duration, and location of ERK activation change between positive and negative selection 8, 32, which has led to the hypothesis that ERK activation is involved in this decision. Using Sos1(T)−/− and Rasgrp1−/− mice, the RasGEFs that are responsible for Ras-dependent ERK activation in developing
Ras and ERK signaling in peripheral lymphocytes
Although the requirements for Ras-dependent ERK activation are well defined during thymocyte development, RasGEF-dependent signaling does not seem to fully explain TCR-dependent ERK activation in peripheral T cells. Knockout, knockdown, and mutational studies in murine CD8+ T cells [52], Jurkat T cells 18, 24, or human T cells 24, 28 have shown that signaling via RasGRP1 accounts for ∼50% of TCR-stimulated ERK activation in peripheral T cells. However, whether Sos1 and Sos2 play a role in
LAT-Y136F knock-in mice have enhanced ERK phosphorylation
We [12] and another laboratory [5] have independently generated and characterized mice with a germline mutation in the PLC-γ1 binding site of LAT (LAT-Y136F mice). LAT-Y136F mice show an early (DN3) block in thymocyte development; however, with age, these mice develop an overwhelming T helper (TH)2 CD4+ T cell lymphoproliferation characterized by lymphadenopathy, splenomegaly, and multiorgan lymphocyte infiltration. Consistent with mutation of the PLC-γ1 binding site on LAT, isolated CD4+ T
Bam32−PLC-γ1−PAK1 complexes contribute to normal TCR-stimulated, Ras-independent ERK activation
In T cells, the Bam32−PLC-γ1−PAK1 complex works in a cooperative manner to activate the Raf−MEK−ERK kinase cascade independently of Ras. In Bam32-deficient CD4+ T cells, it has been shown that TCR-stimulated ERK phosphorylation depends both on Ras-dependent and Bam32-dependent (but Ras-independent) signaling pathways [29], because overexpression of dominant-negative Ras (dnRas) or Bam32 deletion leads to similar reductions in TCR-stimulated ERK activation. Furthermore, the effects of Bam32
PLC-γ1-independent, Ras-dependent ERK activation
Bam32-dependent, Ras-independent signaling [29] does not completely account for ERK hyperactivation in LAT-Y136F mice [54]. Furthermore, biochemical assessment of isolated LAT-Y136F CD4+ T cells shows basal Ras hyperactivation [55], suggesting that signaling by one or more RasGEFs is dysregulated in these cells. RasGRP1 activation normally depends on PLC-γ1-dependent DAG formation and should be defective in LAT-Y136F mice, therefore, Sos1/2 signaling, perhaps via alternative LAT-independent
Concluding remarks
It is well established that TCR-dependent Ras and ERK activation are crucial for both normal intrathymic T cell development and mature T cell function. Developmental studies in mice lacking multiple RasGEFs have shown us that Ras- and ERK-dependent signals are important to drive pre-TCR-dependent proliferation at the β selection checkpoint and TCR-dependent thymocyte selection. However, the relative importance of different RasGEFs differs depending on the developmental stage. Downstream of the
Acknowledgments
We would like to thank Connie Sommers and Lakshmi Balagopalan for helpful suggestions and careful reading of the manuscript. This research was supported by the Intramural Research Program of the NIH, CCR, NCI.
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