The Src family kinase Lck is crucial for initiation of T cell antigen receptor (TCR) signaling. Lck is tightly controlled to prevent erroneous immune activation, yet allows rapid responses over a range of sensitivities to antigens. Here, using an analog-sensitive Csk we report that Lck is dynamically controlled by a Csk:CD45-controlled equilibrium in T cells. By rapidly inhibiting Csk, we show that changes in this equilibrium are sufficient for activation of the canonical TCR signaling pathways independent of TCR stimulation. The activated signaling pathways show sustained and marked hyperphosphorylation, revealing a feedback circuit that is sensitive to basal signaling activity and is capable of adapting to changes in basal signal transduction machinery. We identify the inhibitory adaptor molecule Dok-1 as a candidate in the adaptive response to alterations in basal signaling activity. Our results also suggest a novel role for Csk in terminating or dampening of TCR signals.
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