T细胞受体
细胞生物学
蛋白质酪氨酸磷酸酶
磷酸化
生物
磷酸酶
信号转导
T细胞
激酶
酪氨酸激酶
细胞毒性T细胞
分子生物学
化学
生物化学
免疫学
免疫系统
体外
作者
Alexandre Poirier,João V. S. Ormonde,Isabelle Aubry,Belma Melda Abidin,Chu-Han Feng,Zuzet Martínez-Córdova,Ana Maria Hincapie,Chenyue Wu,Luis‐Alberto Pérez‐Quintero,Chia-Lin Wang,Anne‐Claude Gingras,Joaquı́n Madrenas,Michel L. Tremblay
出处
期刊:Science Signaling
[American Association for the Advancement of Science]
日期:2024-01-02
卷期号:17 (817)
被引量:4
标识
DOI:10.1126/scisignal.adg4422
摘要
Thousand-and-one–amino acid kinase 3 (TAOK3) is a serine and threonine kinase that belongs to the STE-20 family of kinases. Its absence reduces T cell receptor (TCR) signaling and increases the interaction of the tyrosine phosphatase SHP-1, a major negative regulator of proximal TCR signaling, with the kinase LCK, a component of the core TCR signaling complex. Here, we used mouse models and human cell lines to investigate the mechanism by which TAOK3 limits the interaction of SHP-1 with LCK. The loss of TAOK3 decreased the survival of naïve CD4 + T cells by dampening the transmission of tonic and ligand-dependent TCR signaling. In mouse T cells, Taok3 promoted the secretion of interleukin-2 (IL-2) in response to TCR activation in a manner that depended on Taok3 gene dosage and on Taok3 kinase activity. TCR desensitization in Taok3 −/− T cells was caused by an increased abundance of Shp-1, and pharmacological inhibition of Shp-1 rescued the activation potential of these T cells. TAOK3 phosphorylated threonine-394 in the phosphatase domain of SHP-1, which promoted its ubiquitylation and proteasomal degradation. The loss of TAOK3 had no effect on the abundance of SHP-2, which lacks a residue corresponding to SHP-1 threonine-394. Modulation of SHP-1 abundance by TAOK3 thus serves as a rheostat for TCR signaling and determines the activation threshold of T lymphocytes.
科研通智能强力驱动
Strongly Powered by AbleSci AI