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Proc Natl Acad Sci U S A. 2009 Sep 22;106(38):16345-50. doi: 10.1073/pnas.0908593106. Epub 2009 Sep 14.

Gasp, a Grb2-associating protein, is critical for positive selection of thymocytes.

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1
Department of Pathology and Infectious Diseases, International Medical Center of Japan, 1-21-1 Toyama, Shinjuku, Tokyo 162-8655, Japan.

Abstract

T cells develop in the thymus through positive and negative selection, which are responsible for shaping the T cell receptor (TCR) repertoire. To elucidate the molecular mechanisms involved in selection remains an area of intense interest. Here, we identified and characterized a gene product Gasp (Grb2-associating protein, also called Themis) that is critically required for positive selection. Gasp is a cytosolic protein with no known functional motifs that is expressed only in T cells, especially immature CD4/CD8 double positive (DP) thymocytes. In the absence of Gasp, differentiation of both CD4 and CD8 single positive cells in the thymus was severely inhibited, whereas all other TCR-induced events such as beta-selection, negative selection, peripheral activation, and homeostatic proliferation were unaffected. We found that Gasp constitutively associates with Grb2 via its N-terminal Src homology 3 domain, suggesting that Gasp acts as a thymocyte-specific adaptor for Grb2 or regulates Ras signaling in DP thymocytes. Collectively, we have described a gene called Gasp that is critical for positive selection.

PMID:
19805304
PMCID:
PMC2752560
DOI:
10.1073/pnas.0908593106
[Indexed for MEDLINE]
Free PMC Article
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