TCR‐mediated Erk activation does not depend on Sos and Grb2 in peripheral human T cells

Warnecke, Nicole; Poltorak, Mateusz; Kowtharapu, Bhavani S.; Arndt, Boerge; Stone, James C.; Schraven, Burkhart; Simeoni, Luca

doi:10.1038/embor.2012.17

Cited by 31 publications

(43 citation statements)

References 24 publications

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“…Such observations further point out the potential overlapping role of the Sos isoforms during the latter stages of T-cell development, although they could also be a consequence of the disruption or early thymocyte maturation occurring in the DKO mice. The data from our present BM transplantation experiments, together with the recent demonstration of Sos-independent, TCR-mediated Erk activation in peripheral human T cells (35), favor the second possibility, although a more definitive mechanistic answer requires further investigations. Similarly, analysis of the distribution of maturation-associated B-cell subsets in the spleen and PB also showed that only combined disruption of the two Sos proteins leads to a clear alteration of all subsets of mature B lymphocytes but marginal-zone B cells, except for slightly decreased BT2 counts in the spleens of Sos1 and Sos2 single-KO mice.…”

Section: Discussionmentioning

confidence: 64%

Functional Redundancy of Sos1 and Sos2 for Lymphopoiesis and Organismal Homeostasis and Survival

Baltanás

Pérez-Andrés

Ginel-Picardo

et al. 2013

Molecular and Cellular Biology

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dSos1 and Sos2 are ubiquitously expressed, universal Ras guanine nucleotide exchange factors (Ras-GEFs) acting in multiple signal transduction pathways activated by upstream cellular kinases. The embryonic lethality of Sos1 null mutants has hampered ascertaining the specific in vivo contributions of Sos1 and Sos2 to processes controlling adult organism survival or development of hematopoietic and nonhematopoietic organs, tissues, and cell lineages. Here, we generated a tamoxifen-inducible Sos1-null mouse strain allowing analysis of the combined disruption of Sos1 and Sos2 (Sos1/2) during adulthood. Sos1/2 double-knockout (DKO) animals died precipitously, whereas individual Sos1 and Sos2 knockout (KO) mice were perfectly viable. A reduced percentage of total bone marrow precursors occurred in single-KO animals, but a dramatic depletion of B-cell progenitors was specifically detected in Sos1/2 DKO mice. We also confirmed a dominant role of Sos1 over Sos2 in early thymocyte maturation, with almost complete thymus disappearance and dramatically higher reduction of absolute thymocyte counts in Sos1/2 DKO animals. Absolute counts of mature B and T cells in spleen and peripheral blood were unchanged in single-KO mutants, while significantly reduced in Sos1/2 DKO mice. Our data demonstrate functional redundancy between Sos1 and Sos2 for homeostasis and survival of the full organism and for development and maturation of T and B lymphocytes.

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Section: Discussionmentioning

confidence: 64%

Functional Redundancy of Sos1 and Sos2 for Lymphopoiesis and Organismal Homeostasis and Survival

Baltanás

Pérez-Andrés

Ginel-Picardo

et al. 2013

Molecular and Cellular Biology

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“…We have also described digital ERK activation patterns for TCR-stimulated peripheral T cells in the past (10). Recently, SOS1 has been suggested to be of more limited importance in TCR-induced ERK activation in peripheral T cells (78), although FACS patterns of ERK activation were not examined in this study. Future studies should address the question of whether differences in SOS-mediated ERK activation with the various experimental models are a reflection of compensatory mechanisms or due to the developmental stage of the cell population in the analysis.…”

Section: Fig 10mentioning

confidence: 98%

Activation of Extracellular Signal-Regulated Kinase but Not of p38 Mitogen-Activated Protein Kinase Pathways in Lymphocytes Requires Allosteric Activation of SOS

et al. 2013

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Thymocytes convert graded T cell receptor (TCR) signals into positive selection or deletion, and activation of extracellular signal-related kinase (ERK), p38, and Jun N-terminal protein kinase (JNK) mitogen-activated protein kinases (MAPKs) has been postulated to play a discriminatory role. Two families of Ras guanine nucleotide exchange factors (RasGEFs), SOS and RasGRP, activate Ras and the downstream RAF-MEK-ERK pathway. The pathways leading to lymphocyte p38 and JNK activation are less well defined. We previously described how RasGRP alone induces analog Ras-ERK activation while SOS and RasGRP cooperate to establish bimodal ERK activation. Here we employed computational modeling and biochemical experiments with model cell lines and thymocytes to show that TCR-induced ERK activation grows exponentially in thymocytes and that a W729E allosteric pocket mutant, SOS1, can only reconstitute analog ERK signaling. In agreement with RasGRP allosterically priming SOS, exponential ERK activation is severely decreased by pharmacological or genetic perturbation of the phospholipase C␥ (PLC␥)-diacylglycerol-RasGRP1 pathway. In contrast, p38 activation is not sharply thresholded and requires high-level TCR signal input. Rac and p38 activation depends on SOS1 expression but not allosteric activation. Based on computational predictions and experiments exploring whether SOS functions as a RacGEF or adaptor in Rac-p38 activation, we established that the presence of SOS1, but not its enzymatic activity, is critical for p38 activation.

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“…RasGRP1 will in turn enhance the generation of active Ras leading to the activation of the Raf-Mek-Erk cascade. However, for sustained Ras signaling and T-cell activation the activity of Sos1 is also required (Roose et al, 2007;Das et al, 2009;Warnecke et al, 2012;Poltorak et al, 2014).…”

Section: Diversification Of the Signal: The Lat Signalosomementioning

confidence: 99%

Redox regulation of T-cell receptor signaling

Simeoni

Bogeski

2015

Biological Chemistry

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T-cell receptor (TCR) triggering by antigens activates a sophisticated intracellular signaling network leading to transcriptional activation, proliferation and differentiation of T cells. These events ultimately culminate in adaptive immune responses. Over recent years it has become evident that reactive oxygen species (ROS) play an important role in T-cell activation. It is now clear that ROS are involved in the regulation of T-cell mediated physiological and pathological processes. Upon TCR triggering, T cells produce oxidants, which originate from different cellular sources. In addition, within inflamed tissues, T cells are exposed to exocrine ROS produced by activated phagocytes or other ROS-producing cells. Oxidative modifications can have different effects on T-cell function. Indeed, they can stimulate T-cell activation but they can be also detrimental. These opposite effects of oxidation likely depend on different factors such as ROS concentration and source and also on the differentiation status of the T cells. Despite the well-stablished fact that ROS represent important modulators of T-cell activation, the precise molecular mechanisms of their action are far from clear. Here, we summarize the present knowledge on redox regulation of T-cell function with a particular emphasis on the redox regulation of TCR signaling.

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TCR‐mediated Erk activation does not depend on Sos and Grb2 in peripheral human T cells

Cited by 31 publications

References 24 publications

Functional Redundancy of Sos1 and Sos2 for Lymphopoiesis and Organismal Homeostasis and Survival

Functional Redundancy of Sos1 and Sos2 for Lymphopoiesis and Organismal Homeostasis and Survival

Activation of Extracellular Signal-Regulated Kinase but Not of p38 Mitogen-Activated Protein Kinase Pathways in Lymphocytes Requires Allosteric Activation of SOS

Redox regulation of T-cell receptor signaling

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