Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication

DOI

10.4049/jimmunol.1203389

Type

Journal article

Journal

J Immunol

Publication Date

01/04/2013

Volume

190

Pages

3749 - 3756

Keywords

Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Cell Adhesion Molecules, Cell Line, GRB2 Adaptor Protein, Humans, Immunological Synapses, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Molecular Sequence Data, Phosphorylation, Protein Binding, Protein Interaction Domains and Motifs, Sequence Alignment, Thymocytes, ZAP-70 Protein-Tyrosine Kinase