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Molecular and Cellular Biology, November 2006, p. 7892-7900, Vol. 26, No. 21
0270-7306/06/$08.00+0     doi:10.1128/MCB.00968-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Lck SH3 Domain Function Is Required for T-Cell Receptor Signals Regulating Thymocyte Development{triangledown}

Meghan L. Rudd, Alymarie Tua-Smith, and David B. Straus*

Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, Virginia

Received 31 May 2006/ Returned for modification 18 June 2006/ Accepted 15 August 2006

Thymocyte development is shaped by signals from the T-cell antigen receptor. The strength of receptor signaling determines developmental progression as well as deletion of self-reactive T cells. Receptor stimulation of the extracellular signal-regulated kinase (ERK) pathway plays an important regulatory role during thymocyte development. However, it is unclear how differences in receptor signaling are translated into distinctive activation of the ERK pathway. We have investigated the potential role of the Lck tyrosine kinase in regulating intracellular signaling during thymocyte development. While Lck is known to be critical for initial T-cell receptor signaling events, it may have an independent role in regulating intracellular signaling through the function of its SH3 domain. To determine whether such a regulatory mechanism functions during thymocyte development, we generated mice in which the normal lck allele is replaced with an lck SH3 domain mutant. Analysis of these mice revealed that both early thymocyte development and maturation of CD4+ and CD8+ lineages is impaired. Investigation of thymocyte responses to antigen receptor stimulation showed a significant reduction in proliferation and ERK pathway activation, although initial signaling events were intact. These findings indicate that Lck SH3 domain function may provide a means to independently couple receptor signaling to regulation of the ERK pathway during thymocyte development.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Box 980678, Virginia Commonwealth University, Richmond, VA 23298. Phone: (804) 628-0247. Fax: (804) 828-9946. E-mail: dbstraus{at}vcu.edu.

{triangledown} Published ahead of print on 21 August 2006.

Molecular and Cellular Biology, November 2006, p. 7892-7900, Vol. 26, No. 21
0270-7306/06/$08.00+0     doi:10.1128/MCB.00968-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Falahati, R., Leitenberg, D. (2008). Selective Regulation of TCR Signaling Pathways by the CD45 Protein Tyrosine Phosphatase during Thymocyte Development. J. Immunol. 181: 6082-6091 [Abstract] [Full Text]  
  • Li, M., Ong, S. S., Rajwa, B., Thieu, V. T., Geahlen, R. L., Harrison, M. L. (2008). The SH3 Domain of Lck Modulates T-Cell Receptor-Dependent Activation of Extracellular Signal-Regulated Kinase through Activation of Raf-1. Mol. Cell. Biol. 28: 630-641 [Abstract] [Full Text]  


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