Details

Autor(en) / Beteiligte

• Paster, Wolfgang
• Brockmeyer, Claudia
• Fu, Guo
• Simister, Philip C
• de Wet, Ben
• Martinez-Riaño, Ana
• Hoerter, John A H
• Feller, Stephan M
• Wülfing, Christoph
• Gascoigne, Nicholas R J
• Acuto, Oreste

Titel

GRB2-mediated recruitment of THEMIS to LAT is essential for thymocyte development

Ist Teil von

• The Journal of immunology (1950), 2013-04, Vol.190 (7), p.3749-3756

Ort / Verlag

United States: AAI

Erscheinungsjahr

2013

Quelle

MEDLINE

Beschreibungen/Notizen

• Thymocyte-expressed molecule involved in selection (THEMIS) is a recently identified regulator of thymocyte positive selection. THEMIS's mechanism of action is unknown, and whether it has a role in TCR-proximal signaling is controversial. In this article, we show that THEMIS and the adapter molecule growth factor receptor-bound protein 2 (GRB2) associate constitutively through binding of a conserved PxRPxK motif within the proline-rich region 1 of THEMIS to the C-terminal SH3-domain of GRB2. This association is indispensable for THEMIS recruitment to the immunological synapse via the transmembrane adapter linker for activation of T cells (LAT) and for THEMIS phosphorylation by Lck and ZAP-70. Two major sites of tyrosine phosphorylation were mapped to a YY-motif close to proline-rich region 1. The YY-motif was crucial for GRB2 binding, suggesting that this region of THEMIS might control local phosphorylation-dependent conformational changes important for THEMIS function. Finally, THEMIS binding to GRB2 was required for thymocyte development. Our data firmly assign THEMIS to the TCR-proximal signaling cascade as a participant in the LAT signalosome and suggest that the THEMIS-GRB2 complex might be involved in shaping the nature of Ras signaling, thereby governing thymic selection.