Feedback Circuits Monitor and Adjust Basal Lck-Dependent Events in T Cell Receptor Signaling

Sci. Signal., 13 September 2011
Vol. 4, Issue 190, p. ra59
DOI: 10.1126/scisignal.2001893

Feedback Circuits Monitor and Adjust Basal Lck-Dependent Events in T Cell Receptor Signaling

  1. Jamie R. Schoenborn1,*,
  2. Ying Xim Tan1,
  3. Chao Zhang2,
  4. Kevan M. Shokat2,3, and
  5. Arthur Weiss1,3,
  1. 1Rosalind Russell Medical Research Center for Arthritis, Division of Rheumatology, Department of Medicine, University of California, San Francisco, CA 94143, USA.
  2. 2Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143, USA.
  3. 3Howard Hughes Medical Institute.
  1. To whom correspondence should be addressed. E-mail: aweiss{at}medicine.ucsf.edu
  • * Present address: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.

Abstract

The Src family kinase Lck is crucial for the initiation of TCR signaling. The activity of Lck is tightly controlled to prevent erroneous immune activation, yet it enables rapid cellular responses over a range of sensitivities to antigens. Here, in experiments with an analog-sensitive variant of the tyrosine kinase Csk, we report that Lck in T cells is dynamically controlled by an equilibrium between Csk and the tyrosine phosphatase CD45. By rapidly inhibiting Csk, we showed that changes in this equilibrium were sufficient to activate canonical TCR signaling pathways independently of ligand binding to the TCR. The activated signaling pathways showed sustained and enhanced phosphorylation compared to that in TCR-stimulated cells, revealing a feedback circuit that was sensitive to the basal signaling machinery. We identified the inhibitory adaptor molecule Dok-1 (downstream of kinase 1) as a candidate that may respond to alterations in basal signaling activity. Our results also suggest a role for Csk in the termination or dampening of TCR signals.

Citation:

J. R. Schoenborn, Y. X. Tan, C. Zhang, K. M. Shokat, and A. Weiss, Feedback Circuits Monitor and Adjust Basal Lck-Dependent Events in T Cell Receptor Signaling. Sci. Signal. 4, ra59 (2011).

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Sci Signal 8, ra49-ra49 (19 May 2015)

Focal Adhesion Kinase Negatively Regulates Lck Function Downstream of the T Cell Antigen Receptor
N. M. Chapman, S. F. Connolly, E. L. Reinl, and J. C. D. Houtman
J. Immunol. 191, 6208-6221 (15 December 2013)

Differential Polarization of C-Terminal Src Kinase between Naive and Antigen-Experienced CD8+ T Cells
J. G. Borger, A. Filby, and R. Zamoyska
J. Immunol. 190, 3089-3099 (1 April 2013)

A Phospholipase C-{gamma}1-Independent, RasGRP1-ERK-Dependent Pathway Drives Lymphoproliferative Disease in Linker for Activation of T Cells-Y136F Mutant Mice
R. L. Kortum, A. K. Rouquette-Jazdanian, M. Miyaji, R. K. Merrill, E. Markegard, J. M. Pinski, A. Wesselink, N. N. Nath, C. P. Alexander, W. Li et al.
J. Immunol. 190, 147-158 (1 January 2013)

Novel Tools to Dissect the Dynamic Regulation of TCR Signaling by the Kinase Csk and the Phosphatase CD45
Y. X. Tan, J. Zikherman, and A. Weiss
Cold Spring Harb Symp Quant Biol 78, 131-139 (1 January 2013)

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