GRB2-Mediated Recruitment of THEMIS to LAT Is Essential for Thymocyte Development
GRB2-Mediated Recruitment of THEMIS to LAT Is Essential for Thymocyte Development
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DOI：
10.4049/jimmunol.1203389
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发表时间：
2013-04-01
影响因子：
4.4
通讯作者：
Acuto, Oreste
中科院分区：
文献类型：
--
作者：
Paster, Wolfgang;Brockmeyer, Claudia;Acuto, Oreste
胸腺细胞表达分子参与选择（THEMIS）是最近发现的胸腺细胞阳性选择的调节因子。THEMIS的作用机制尚不清楚，它是否在tcr -近端信号传导中起作用尚存争议。在本文中，我们发现THEMIS和适配器分子生长因子受体结合蛋白2 （GRB2）通过将THEMIS富含脯氨酸区域1内的保守PxRPxK基序结合到GRB2的c端sh3结构域而组成性地结合。这种关联对于THEMIS通过跨膜适配器连接器募集到免疫突触以激活T细胞（LAT）以及被Lck和ZAP-70磷酸化是必不可少的。酪氨酸磷酸化的两个主要位点被定位到靠近脯氨酸富集区1的yy -基序。yy -基序对GRB2结合至关重要，这表明THEMIS的这个区域可能控制着对THEMIS功能重要的局部磷酸化依赖的构象变化。最后，胸腺细胞的发育需要THEMIS与GRB2结合。我们的数据明确地将THEMIS定位于tcr -近端信号级联，作为LAT信号体的参与者，并表明THEMIS- grb2复合体可能参与塑造Ras信号的性质，从而控制胸腺选择。中华免疫学杂志，2013,29(1):349 - 356。
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. The Journal of Immunology, 2013, 190: 3749-3756.