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Molecular and Cellular Biology, May 2004, p. 4581-4592, Vol. 24, No. 10
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.10.4581-4592.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

The Adapter Molecule Sin Regulates T-Cell-Receptor-Mediated Signal Transduction by Modulating Signaling Substrate Availability

Luzhou Xing,1,{dagger} Laura T. Donlin,1,{dagger} Rebecca H. Miller,2 and Konstantina Alexandropoulos1*

Department of Pharmacology,1 Department of Nutrition, College of Physicians and Surgeons of Columbia University, New York, New York 100322

Received 11 August 2003/ Returned for modification 3 October 2003/ Accepted 14 February 2004

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.

* Corresponding author. Mailing address: Department of Pharmacology, College of Physicians and Surgeons of Columbia University, 630 West 168th St., New York, NY 10032. Phone: (212) 305-2705. Fax: (212) 305-8780. E-mail: ka141{at}columbia.edu.

{dagger} L.X. and L.T.D. made equal contributions to this work.

Molecular and Cellular Biology, May 2004, p. 4581-4592, Vol. 24, No. 10
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.10.4581-4592.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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