| First Author | Paster W | Year | 2013 |
| Journal | J Immunol | Volume | 190 |
| Issue | 7 | Pages | 3749-56 |
| PubMed ID | 23460737 | Mgi Jnum | J:194815 |
| Mgi Id | MGI:5474872 | Doi | 10.4049/jimmunol.1203389 |
| Citation | Paster W, et al. (2013) GRB2-Mediated Recruitment of THEMIS to LAT Is Essential for Thymocyte Development. J Immunol 190(7):3749-56 |
| abstractText | 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. |
