B‐Raf‐mediated signaling pathway regulates T cell development

Tsukamoto, Hirotake; Irie, Atsushi; Senju, Satoru; Hatzopoulos, Antonis K.; Wojnowski, Leszek; Nishimura, Yasuharu

doi:10.1002/eji.200737430

Cited by 13 publications

(15 citation statements)

References 44 publications

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“…These results suggested that sorafenib should suppress activation of T cells after TCR stimulation. As previous report, MAPK, JNK, and Raf kinases are involved in activation and function of T cells 28, 29, and these kinases can be inhibited by sorafenib. Nevertheless, in this study, we found that at lower doses (1 or 5 µM), sorafenib effectively suppressed induction of Tregs without reducing CD25 expression and at the dose of 5 µM, SMAD and non‐SMAD pathways were down‐regulated significantly.…”

Section: Discussionsupporting

confidence: 72%

Sorafenib reduces hepatic infiltrated regulatory T cells in hepatocellular carcinoma patients by suppressing TGF‐beta signal

Wang

Yuan³

et al. 2012

Journal of Surgical Oncology

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Section: Discussionsupporting

confidence: 72%

Sorafenib reduces hepatic infiltrated regulatory T cells in hepatocellular carcinoma patients by suppressing TGF‐beta signal

Wang

Yuan³

et al. 2012

Journal of Surgical Oncology

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“…In line with this, it was shown that B-Raf is activated by TCR signaling (4,20,21,55), that B-Raf deficiency in T cells results in developmental defects in the mouse (21), and that B-Raf is critical for TCR-mediated ERK activation in T cells from rheumatoid arthritis patients (56). In this study, we show that, upon TCR stimulation, the inhibitory N-terminal 14-3-3 binding site of B-Raf (S365) was dephosphorylated, and B-Raf was hyperphosphorylated, again showing that B-Raf is a downstream-signaling molecule of the TCR.…”

Section: Discussionmentioning

confidence: 56%

“…TCR-induced activation of Raf-1 leads to a transient Erk signal, whereas activation by B-Raf leads to sustained Erk activation in T cells (20,21). Although sustained Erk signaling is crucial for IL-2 production by T cells (20,22,23), it is not understood how TCR triggering leads to B-Raf activation.…”

mentioning

confidence: 99%

Kidins220/ARMS Associates with B-Raf and the TCR, Promoting Sustained Erk Signaling in T Cells

Deswal

Meyer

Fiala

et al. 2013

The Journal of Immunology

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The activation kinetics of MAPK Erk are critical for T cell development and activation. In particular, sustained Erk signaling is required for T cell activation and effector functions, such as IL-2 production. Although Raf-1 triggers transient Erk activation, B-Raf is implicated in sustained Erk signaling after TCR stimulation. In this study, we show that B-Raf is dephosphorylated on its inhibitory serine 365 upon TCR triggering. However, it is unknown how B-Raf activation is coupled to the TCR. Using mass spectrometry, we identified protein kinase D–interacting substrate of 220 kDa (Kidins220)/ankyrin repeat-rich membrane spanning protein, mammalian target of rapamycin, Rictor, Dock2, and GM130 as novel B-Raf interaction partners. We focused on Kidins220, a protein that has been studied in neuronal cells and found that it associated with the pre-TCR, αβTCR, and γδTCR. Upon prolonged TCR stimulation, the Kidins220–TCR interaction was reduced, as demonstrated by immunoprecipitation and proximity ligation assays. We show that Kidins220 is required for TCR-induced sustained, but not transient, Erk activation. Consequently, induction of the immediate early gene products and transcription factors c-Fos and Erg-1 was blocked, and upregulation of the activation markers CD69, IL-2, and IFN-γ was reduced. Further, Kidins220 was required for optimal calcium signaling. In conclusion, we describe Kidins220 as a novel TCR-interacting protein that couples B-Raf to the TCR. Kidins220 is mandatory for sustained Erk signaling; thus, it is crucial for TCR-mediated T cell activation.

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“…In cells that are wild-type for BRAF, these inhibitors may paradoxically activate ERK signaling via transactivation of RAF dimers (9–12). This paradoxical activation depends upon signaling upstream of RAF, as in the case of hyperactivating RAS mutations.…”

Section: Discussionmentioning

confidence: 99%

Paradoxical Activation of T Cells via Augmented ERK Signaling Mediated by a RAF Inhibitor

Callahan

Masters

Pratilas

et al. 2014

Cancer Immunology Research

105

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RAF inhibitors selectively block ERK signaling in BRAF-mutant melanomas and have defined a genotype-guided approach to care for this disease. RAF inhibitors have the opposite effect in BRAF wild-type tumor cells, where they cause hyperactivation of ERK signaling. Here, we predict that RAF inhibitors can enhance T cell activation, based upon the observation that these agents paradoxically activate ERK signaling in BRAF wild-type cells. To test this hypothesis, we have evaluated the effects of the RAF inhibitor BMS908662 on T cell activation and signaling in vitro and in vivo. We observe that T cell activation is enhanced in a concentration-dependent manner and that this effect corresponds with increased ERK signaling, consistent with paradoxical activation of the pathway. Furthermore, we find that the combination of BMS908662 with CTLA-4 blockade in vivo potentiates T cell expansion, corresponding with hyperactivation of ERK signaling in T cells detectable ex vivo. Lastly, this combination demonstrates superior anti-tumor activity, compared to either agent alone, in two transplantable tumor models. This study provides clear evidence that RAF inhibitors can modulate T cell function by potentiating T cell activation in vitro and in vivo. Paradoxical activation of ERK signaling in T cells offers one mechanism to explain the enhanced antitumor activity seen when RAF inhibitors are combined with CTLA-4 blockade in preclinical models.

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B‐Raf‐mediated signaling pathway regulates T cell development

Cited by 13 publications

References 44 publications

Sorafenib reduces hepatic infiltrated regulatory T cells in hepatocellular carcinoma patients by suppressing TGF‐beta signal

Sorafenib reduces hepatic infiltrated regulatory T cells in hepatocellular carcinoma patients by suppressing TGF‐beta signal

Kidins220/ARMS Associates with B-Raf and the TCR, Promoting Sustained Erk Signaling in T Cells

Paradoxical Activation of T Cells via Augmented ERK Signaling Mediated by a RAF Inhibitor

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