Woods M L, Kivens W J, Adelsman M A, Qiu Y, August A, Shimizu Y
Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
EMBO J. 2001 Mar 15;20(6):1232-44. doi: 10.1093/emboj/20.6.1232.
Stimulation of T cells via the CD3--T-cell receptor (TCR) complex results in rapid increases in beta 1 integrin-mediated adhesion via poorly defined intracellular signaling events. We demonstrate that TCR-mediated activation of beta 1 integrins requires activation of the Tec family tyrosine kinase Itk and phosphatidylinositol 3-kinase (PI 3-K)-dependent recruitment of Itk to detergent-insoluble glycosphingolipid-enriched microdomains (DIGs) via binding of the pleckstrin homology domain of Itk to the PI 3-K product PI(3,4,5)-P(3). Activation of PI 3-K and the src family kinase Lck, via stimulation of the CD4 co-receptor, can initiate beta 1 integrin activation that is dependent on Itk function. Targeting of Itk specifically to DIGs, coupled with CD4 stimulation, can also activate beta 1 integrin function independently of TCR stimulation. Changes in beta 1 integrin function mediated by TCR activation of Itk are also accompanied by Itk-dependent modulation of the actin cytoskeleton. Thus, TCR-mediated activation of beta 1 integrins involves membrane relocalization and activation of Itk via coordinate action of PI 3-K and a src family tyrosine kinase.
通过CD3-T细胞受体（TCR）复合体刺激T细胞，会经由定义不明的细胞内信号事件，导致β1整合素介导的黏附迅速增加。我们证明，TCR介导的β1整合素激活需要Tec家族酪氨酸激酶Itk的激活，以及磷脂酰肌醇3激酶（PI 3-K）依赖的Itk通过其pleckstrin同源结构域与PI 3-K产物PI(3,4,5)-P(3)结合而募集到去污剂不溶性富含糖鞘脂微区（DIGs）。通过刺激CD4共受体激活PI 3-K和src家族激酶Lck，可启动依赖于Itk功能的β1整合素激活。将Itk特异性靶向DIGs，再结合CD4刺激，也可独立于TCR刺激激活β1整合素功能。Itk的TCR激活介导的β1整合素功能变化还伴有Itk依赖的肌动蛋白细胞骨架调节。因此，TCR介导的β1整合素激活涉及通过PI 3-K和src家族酪氨酸激酶的协同作用使Itk发生膜重新定位和激活。
