Itk Promotes the Integration of TCR and CD28 Costimulation through Its Direct Substrates SLP-76 and Gads.
Itk Promotes the Integration of TCR and CD28 Costimulation through Its Direct Substrates SLP-76 and Gads.
复制标题
DOI：
10.4049/jimmunol.2001053
复制
发表时间：
2021-05-15
期刊：
影响因子：
--
通讯作者：
Yablonski D
中科院分区：
文献类型：
--
作者：
Hallumi E;Shalah R;Lo WL;Corso J;Oz I;Beach D;Wittman S;Isenberg A;Sela M;Urlaub H;Weiss A;Yablonski D
The costimulatory receptor, CD28, synergizes with the T cell antigen receptor (TCR) to promote IL-2 production, cell survival and proliferation; yet the obligatory interdependence of TCR and CD28 signaling is not well understood. Upon TCR stimulation, Gads, a Grb2-family adaptor, bridges the interaction of two additional adaptors, LAT and SLP-76, to form a TCR-induced effector signaling complex. SLP-76 binds the Tec-family tyrosine kinase, Itk, which phosphorylates SLP-76 Y173 and PLC-γ1 Y783. Here, we identified TCR-inducible, Itk-mediated phosphorylation of Gads Y45, in a human T cell line and in mouse primary T cells. Y45 is found within the N-terminal SH3 domain of Gads, an evolutionarily conserved domain with no known signaling function. Gads Y45 phosphorylation depended on the interaction of Gads with SLP-76, and on the dimerization-dependent binding of Gads to phospho-LAT. We provide evidence that Itk acts through SLP-76 and Gads to promote the TCR/CD28-induced activation of the RE/AP transcriptional element from the IL-2 promoter. Two Itk-related features of SLP-76: Y173, and a proline-rich Itk SH3-binding motif on SLP-76, were dispensable for activation of NFAT, but selectively required for the TCR/CD28-induced increase in cytoplasmic and nuclear c-Rel, and consequent RE/AP activation. We provide evidence that unphosphorylated, monomeric Gads mediates an RE/AP-directed inhibitory activity that is mitigated upon Gads dimerization and Y45 phosphorylation. This study illuminates a new regulatory module, in which TCR-induced, Itk-mediated phosphorylation sites on SLP-76 and Gads control the transcriptional response to TCR/CD28 costimulation, thus enforcing the obligatory interdependence of the TCR and CD28 signaling pathways.
登录
查看更多内容
影响因子：
4.8
作者：
Bilal MY;Zhang EY;Dinkel B;Hardy D;Yankee TM;Houtman JC
通讯作者：
Houtman JC
影响因子：
7.2
作者：
Balagopalan, Lakshmi;Coussens, Nathan P.;Sommers, Connie L.
通讯作者：
Sommers, Connie L.
影响因子：
56.9
作者：
FRASER, JD;IRVING, BA;WEISS, A
通讯作者：
WEISS, A
影响因子：
4.8
作者：
Andersen, Thorny Cecilie Bie;Kristiansen, Per Eugen;Spurkland, Anne
通讯作者：
Spurkland, Anne
下调 T 细胞激活的新途径涉及 HPK-1 依赖性在 SLP-76 上招募 14-3-3 蛋白。
影响因子：
15.3
作者：
Di Bartolo, Vincenzo;Montagne, Benjamin;Salek, Mogjiborahman;Jungwirth, Britta;Carrette, Florent;Fourtane, Julien;Sol-Foulon, Nathalie;Michel, Frederique;Schwartz, Olivier;Lehmann, Wolf D.;Acuto, Oreste
通讯作者：
Acuto, Oreste