TCR signaling: the barrier within
Dustin ML, Davis SJ. (2014), Nat Immunol, 15, 136-7
Acute inhibition of the regulatory kinase Csk reveals additional checkpoints for full activation of thymocytes via the T cell antigen receptor.
Key figure: Effects of Csk inhibition and actin disruption on TCR signaling
(a) The actin cortex forms a physical barrier between the membrane and the rest of the cytoplasm. Only the F-actin part of the cortex is presented here. The proteins are drawn to scale; the cytoplasmic domains of TCR-CD3 and Lat, even at their theoretical maximal length (~3.5Å per residue), are occluded by the actin cortex. Scale bar, 10 nm. (b) Role of Csk in the regulation of Lck. The inactive, primed and active isoforms of Lck interconvert through the phosphorylation of Csk and autophosphorylation of Lck and through CD45-mediated dephosphorylation. (c) Signaling thresholds and the effects of global perturbation of receptors. Arrows indicate signaling cascades initiated by Lck-mediated phosphorylation of individual TCRs in the resting state; arrow length corresponds to the depth of the signaling cascade reached (so for a given condition the lengths vary, reflective of stochastic effects): basal signaling (gray); signaling initiated by inhibition of CskAS (purple); or signaling initiated by inhibition of CskAS and disruption of actin (or costimulation via CD38; red). Blue and red dashed lines represent signaling thresholds that correspond to the phosphorylation (p-) of PLC-γ1 and Erk. In the unperturbed cell, the signaling cascades reach neither threshold. Inhibition of CskAS probably globally enhances Lck activity and TCR phosphorylation and thus increases the number of signaling cascades and the probability that at least one cascade breaches the threshold required for the phosphorylation of PLC-γ1. The phosphorylation of Erk also requires disruption of actin, which may enhance the access of PLC-γ1 to substrates in the membrane.