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Programs in Signal Transduction and Stem Cells and Regeneration, Burnham Institute for Medical Research, La Jolla, CA 92037
It is well known that T cell differentiation and maturation in the thymus is tightly controlled at multiple checkpoints. However, the molecular mechanism for the control of this developmental program is not fully understood. A number of protein tyrosine kinases, such as Zap-70, Lck, and Fyn, have been shown to promote signals required for thymocyte development, whereas a tyrosine phosphatase Src homology domain-containing tyrosine phosphatase (Shp)1 has a negative effect in pre-TCR and TCR signaling. We show in this study that Shp2, a close relative of Shp1, plays a positive role in T cell development and functions. Lck-Cre-mediated deletion of Shp2 in the thymus resulted in a significant block in thymocyte differentiation/proliferation instructed by the pre-TCR at the 
selection step, and reduced expansion of CD4+ T cells. Furthermore, mature Shp2–/– T cells showed decreased TCR signaling in vitro. Mechanistically, Shp2 acts to promote TCR signaling through the ERK pathway, with impaired activation of ERK kinase observed in Shp2–/– T cells. Thus, our results provide physiological evidence that Shp2 is a common signal transducer for pre-TCR and TCR in promoting T cell maturation and proliferation.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grant R01 CA78606 (to G.-S.F.).
2 Address correspondence and reprint requests to Dr. Gen-Sheng Feng, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037. E-mail address: gfeng{at}burnham.org
3 Abbreviations used in this paper: DN, double negative; DP, double positive; SP, single positive; KO, knockout; pERK, phosphorylated ERK; WT, wild type.
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