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Updated: Aug 24, 2026
Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
Published on: January 22, 2019
The adapter molecule Sin regulates T-cell-receptor-mediated signal transduction by modulating signaling substrate
Luzhou Xing1, Laura T Donlin, Rebecca H Miller
1Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA.
Abstract:
Engagement of the T-cell receptor (TCR) results in the activation of a multitude of signaling events that regulate the function of T lymphocytes. These signaling events are in turn modulated by adapter molecules, which control the final functional output through the formation of multiprotein complexes. In this report, we identified the adapter molecule Sin as a new regulator of T-cell activation. We found that the expression of Sin in transgenic T lymphocytes and Jurkat T cells inhibited interleukin-2 expression and T-cell proliferation. This inhibitory effect was specific and was due to defective phospholipase C-gamma (PLC-gamma) phosphorylation and activation. In contrast to other adapters that become phosphorylated upon TCR stimulation, Sin was constitutively phosphorylated in resting cells by the Src kinase Fyn and bound to signaling intermediates, including PLC-gamma. In stimulated cells, Sin was transiently dephosphorylated, which coincided with transient dissociation of Fyn and PLC-gamma. Downregulation of Sin expression using Sin-specific short interfering RNA oligonucleotides inhibited transcriptional activation in response to TCR stimulation. Our results suggest that endogenous Sin influences T-lymphocyte signaling by sequestering signaling substrates and regulating their availability and/or activity in resting cells, while Sin is required for targeting these intermediates to the TCR for fast signal transmission during stimulation.
Insights
The adapter molecule Sin regulates T-cell activation by modulating signaling pathways. Sin inhibits interleukin-2 expression and T-cell proliferation by affecting phospholipase C-gamma (PLC-gamma) phosphorylation and activation.
Area of Science:
- Immunology
- Molecular Biology
- Cell Signaling
Background:
- T-cell receptor (TCR) engagement initiates signaling cascades crucial for T lymphocyte function.
- Adapter molecules are key regulators of these signaling events, forming multiprotein complexes.
- The precise role of adapter molecule Sin in T-cell activation remained largely uncharacterized.
Purpose of the Study:
- To identify and characterize the adapter molecule Sin as a novel regulator of T-cell activation.
- To elucidate the mechanism by which Sin influences T-cell signaling pathways.
- To investigate the role of Sin in T-lymphocyte function.
Main Methods:
- Transgenic T lymphocytes and Jurkat T cells were utilized to study Sin expression.
- Short interfering RNA (siRNA) oligonucleotides were employed to downregulate Sin expression.
- Phosphorylation and activation of phospholipase C-gamma (PLC-gamma) were assessed.
- Protein-protein interactions and subcellular localization were examined using biochemical assays.
Main Results:
- Sin expression inhibited interleukin-2 production and T-cell proliferation.
- Sin specifically impaired phospholipase C-gamma (PLC-gamma) phosphorylation and activation.
- Constitutive phosphorylation of Sin by Fyn kinase in resting cells was observed, along with binding to PLC-gamma.
- Sin dephosphorylation and dissociation from Fyn and PLC-gamma occurred upon TCR stimulation.
- Downregulation of Sin using siRNA reduced TCR-induced transcriptional activation.
Conclusions:
- Endogenous Sin acts as a critical regulator of T-lymphocyte signaling.
- Sin sequesters signaling substrates in resting cells, controlling their availability and activity.
- Sin facilitates rapid signal transmission by targeting intermediates to the TCR during stimulation.
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