B-Raf Contributes to Sustained Extracellular Signal-regulated Kinase Activation Associated with Interleukin-2 Production Stimulated through the T Cell Receptor

Tsukamoto, Hirotake; Irie, Atsushi; Nishimura, Yasuharu

doi:10.1074/jbc.m403087200

Cited by 28 publications

(47 citation statements)

References 51 publications

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“…1 and [25]); there might be a relative difficulty to detect B-Raf expression in T cells under conditions in which comparable loading of total protein is done for T cells and PC12 cells. However, supporting our observations, several groups independently reported that B-Raf is expressed in human and murine T cells [24,26,[38][39][40]. Based on our findings and these reports showing B-Raf expression, we have concluded that both murine thymocytes and peripheral T cells express B-Raf, which prompted us to investigate the function of B-Raf in T cells.…”

Section: Discussionsupporting

confidence: 90%

“…Therefore, the DP arrest of thymocytes expressing the mutant Raf protein may be due to interference with B-Raf function, which can be supportive evidence of our results. Furthermore, it was reported that maximal activation of B-Raf requires Ras activation [15], and we have demonstrated that B-Raf activity is regulated by Ras in TCR-stimulated T cells [24]. Based on these results, the defect in thymocyte differentiation from the DP to SP stage (positive selection) in mice expressing a dominant-negative mutant of Ras could be partly explained by impaired B-Raf activation.…”

Section: Discussionsupporting

confidence: 59%

“…Previously we reported that B-Raf activation is regulated by Ras and mediates sustained ERK activation and subsequent IL-2 production upon TCR stimulation in human T cells [22,24]. In addition, enforced expression of B-Raf in mouse CD4 + T cells resulted in augmentation of their proliferation and prevention of anergy induction [25].…”

Section: Introductionmentioning

confidence: 94%

“…No compensatory increase in Raf-1 expression was observed in B-Raf-deficient T cells. B-Raf protein was highly expressed in PC12 cells and B-Raf-transfected Jurkat cells, which were utilized as positive controls [24,28].…”

Section: Expression and Activation Of B-raf In Thymocytesmentioning

confidence: 99%

“…Jurkat cells transfected with B-Raf (or mock-transfected) were prepared as described [24]. Thymic DP and SP cells were purified by cell sorting using a BD FACSVantage (>98% CD4 + CD8 + DP, >95% CD4 + SP or CD8 + SP).…”

Section: Cell Stimulation Western Blotting and In Vitro Kinase Assaymentioning

confidence: 99%

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B‐Raf‐mediated signaling pathway regulates T cell development

et al. 2008

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The activities of the Raf kinase family proteins control extracellular signal-regulated kinase (ERK) activation in many aspects of cellular responses. However, the relative contributions of individual isozymes to cellular functions including T cell responses are still unclear. In addition to Raf-1, another Raf family kinase, B-Raf, is expressed in murine thymocytes and peripheral T cells, and its activation was induced by TCR stimulation. Here, we investigated the function of B-Raf in development of T cells by generating chimeric mice in which a T cell-compromised host was reconstituted with fetal liver-derived cells from embryonic lethal B-Raf-deficient mice. Although B-Raf was dispensable for normal T cell lineage differentiation at the CD4 -CD8 -double-negative stage, thymocytes in the chimeric mice derived from B-Raf -/-cells exhibited a drastic arrest of differentiation at the CD4 + CD8 + double-positive stage, suggesting that B-Raf is crucial for T cell development, especially for the transition to CD4 + and CD8 + singlepositive thymocytes. Regarding intracellular signaling, we found that activation of ERK following TCR stimulation was impaired in the thymocytes from the chimeric mice. In conclusion, we present first evidence for the important role of B-Raf-mediated signaling in T cell development.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 59%

Section: Introductionmentioning

confidence: 94%

Section: Expression and Activation Of B-raf In Thymocytesmentioning

confidence: 99%

Section: Cell Stimulation Western Blotting and In Vitro Kinase Assaymentioning

confidence: 99%

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B‐Raf‐mediated signaling pathway regulates T cell development

et al. 2008

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TCR ligand avidity determines the modeof B‐Raf/Raf‐1/ERK activation leading to the activationof human CD4⁺ T cell clone

et al. 2006

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The interactions between peptide/MHC complexes and their cognate TCR are essential for various T cell responses. However, the relationship between the avidity of TCR ligand and the subsequent intracellular signaling through the TCR is still unclear. To investigate the effects of TCR ligand avidity on TCR-mediated signaling, we established L cells expressing HLA-DR4 molecules covalently linked with agonistic peptide (highaffinity ligand) or altered peptide ligand (APL; low-affinity ligand) at various densities as APC for a cognate human CD4 + T cell clone. Using this system, we demonstrated that the T cell clone stimulated with APL/HLA-DR4 complexes presented at an excessive density provoked the up-regulation of CD69, IL-2 production and proliferation, but no detectable phosphorylation of ZAP-70/LAT/SLP-76. Furthermore, in contrast to the high-affinity stimulation, the low-affinity stimulation evoked delayed and sustained activation of the B-Raf/extracellular signal-regulated kinase (ERK) pathway without Raf-1 activation. The strength and duration of B-Raf/ERK activations closely correlated with the density of the TCR ligand. A knockdown approach confirmed that B-Raf activation was indispensable for the APL-induced T cell responses. These observations suggest that the differences in TCR-peptide/MHC interactions reflect the strength and duration of B-Raf/Raf-1/ERK activation in the human CD4 + T cells.

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Distinct orientation of the alloreactive monoclonal CD8 T cell activation program by three different peptide/MHC complexes

et al. 2006

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We have characterized three different programs of activation for alloreactive CD8 T cells expressing the BM3.3 TCR, their elicitation depending on the characteristics of the stimulating peptide/MHC complex. The high-affinity interaction between the TCR and the K b -associated endogenous peptide pBM1 (INFDFNTI) induced a complete differentiation program into effector cells correlated with sustained ERK activation. The K bm8 variant elicited a partial activation program with delayed T cell proliferation, poor CTL activity and undetectable ERK phosphorylation; this resulted from a low-avidity interaction of TCR BM3.3 with a newly identified endogenous peptide, pBM8 (SQYYYNSL). Interestingly, mismatched pBM1/K bm8 complexes induced a split response in BM3.3 T cells, with total reconstitution of T cell proliferation but defective generation of CTL activity that was correlated with strong but shortened ERK phosphorylation. Crystal structures highlight the molecular basis for the higher stability of pBM8/K bm8 compared to pBM1/K bm8 complexes that exist in two conformers. This study illustrates the importance of the stability of both peptide/MHC and peptide/ MHC-TCR interactions for induction of sustained signaling required to induce optimal CTL effector functions. Subtle allelic structural variations, amplified by peptide selection, may thus orient distinct outcomes of alloreactive TCR-based therapies.

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B-Raf Contributes to Sustained Extracellular Signal-regulated Kinase Activation Associated with Interleukin-2 Production Stimulated through the T Cell Receptor

Cited by 28 publications

References 51 publications

B‐Raf‐mediated signaling pathway regulates T cell development

B‐Raf‐mediated signaling pathway regulates T cell development

TCR ligand avidity determines the modeof B‐Raf/Raf‐1/ERK activation leading to the activationof human CD4⁺ T cell clone

Distinct orientation of the alloreactive monoclonal CD8 T cell activation program by three different peptide/MHC complexes

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B-Raf Contributes to Sustained Extracellular Signal-regulated Kinase Activation Associated with Interleukin-2 Production Stimulated through the T Cell Receptor

Cited by 28 publications

References 51 publications

B‐Raf‐mediated signaling pathway regulates T cell development

B‐Raf‐mediated signaling pathway regulates T cell development

TCR ligand avidity determines the modeof B‐Raf/Raf‐1/ERK activation leading to the activationof human CD4+ T cell clone

Distinct orientation of the alloreactive monoclonal CD8 T cell activation program by three different peptide/MHC complexes

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TCR ligand avidity determines the modeof B‐Raf/Raf‐1/ERK activation leading to the activationof human CD4⁺ T cell clone