Sos1 regulates sustained TCR‐mediated Erk activation

Abstract

The duration and/or the magnitude of Ras-Erk activation are known to be crucial for cell-fate decisions. In T cells, sustained Erk activation correlates with differentiation/proliferation, whereas transient Erk activation parallels with unresponsiveness/apoptosis. The mechanism by which Son of sevenless (Sos) proteins and Ras guanylreleasing protein 1 (RasGRP1) contribute to dynamics of Erk activation in mature T cells is not yet known. Here, we have assessed this issue using stimuli inducing either transient or sustained TCR signaling and RNA interference mediated suppression of Sos1, Sos2, and RasGRP1 expression in primary human T cells. We found that transient Erk activation depends on RasGRP1 but not on Sos. Conversely, sustained Erk signaling and T-cell activation depend on both Sos1 and RasGRP1. In summary, our data show for the first time that the two guanine nucleotide exchange factors expressed in T cells are differentially involved in the regulation of the duration of Erk phosphorylation and T-cell activation.Keywords: Activation kinetics r Ras-Erk activation r RasGRP1 r Sos r Sustained signaling Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionSignaling via the Ras-Erk (where Ras is rat sarcoma) cascade presides over the regulation of a variety of cellular processes such as proliferation, differentiation, migration, and cell death. One of the puzzling aspects of Ras-Erk activation is that it can elicit distinct outcomes even in the same cell type. Recent progress has shown that variations in the duration, the magnitude, and the compartmentalization of Erk activation determine the specificity of the signaling output and the consequent cellular outcome [1].Upon ligation of the TCR, the activation of Ras is thought to be mediated via the action of two guanine nucleotide exchange Correspondence: Dr. Luca Simeoni e-mail: luca.simeoni@med.ovgu.de factors, Ras guanyl-releasing protein 1 (RasGRP1) and Son of sevenless 1 (Sos1). A major step forward in our understanding of the molecular mechanism underlying the regulation of the Ras-Erk cascade in T cells has been recently made [2,3]. Studies based on lymphoid cell lines and in silico simulations have, indeed, shown that Ras activation depends on the coordinated action of Ras-GRP1 and Sos. According to the proposed model, TCR ligation results in the generation of active Ras (RasGTP) exclusively via RasGRP1. However, this initial pool of active Ras is not sufficient to trigger full T-cell activation. Therefore, in order to prime T cells, a prolonged stimulation with the same antigen is required. This will lead to a progressive increase in the amount of intracellular RasGTP until a certain threshold is reached. At this point, Sos comes into play. The pool of RasGTP generated by RasGRP1 primes Sos by binding an allosteric regulatory site thereby activating a positive feedback loop and allowing full T-cell activation. Despite the fact that it is well-characterized how RasGRP1 and Sos orch...

Redox regulation of T-cell receptor signaling

“…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).…”

Identification of Potential Novel Biomarkers and Signaling Pathways Related to Otitis Media Induced by Diesel Exhaust Particles Using Transcriptomic Analysis in an In Vivo System

“…SOS1 is related to signaling transduction involved in cell growth and differentiation regulation by promoting the exchange of Ras-bound GDP with GTP [27]. Specifically, SOS1 regulates several signaling pathways related to T-cell responses [28, 29]. SOS1 knockout mice exhibited impaired T-cell migration via activation of the PI3K/AKT pathway [28].…”

“…SOS1 knockout mice exhibited impaired T-cell migration via activation of the PI3K/AKT pathway [28]. Moreover, SOS1 regulation sustained Erk activation, which is associated with T-cell differentiation and proliferation [29]. …”

Proprotein convertase FURIN regulates T cell receptor-induced transactivation

“…In addition to antigen ligation of TCR, various extracellular stimuli can lead to ERK activation [32,33], which then elicits distinct, occasionally opposite cellular outcomes [34]. ERK is activated by the GTPase Ras, whose activation, in turn, is dependent on RasGRP1 and son of sevenless [35][36][37]. Cleavage-site prediction indicates that FURIN could process RasGRP1 (data not shown) and thus, affect ERK phosphorylation.…”