Tomlinson Michael G, Kane Lawrence P, Su Jennifer, Kadlecek Theresa A, Mollenauer Marianne N, Weiss Arthur
Department of Medicine and Howard Hughes Medical Institute, University of California, San Francisco, California 94143, USA.
Mol Cell Biol. 2004 Mar;24(6):2455-66. doi: 10.1128/MCB.24.6.2455-2466.2004.
The Tec protein tyrosine kinase is the founding member of a family that includes Btk, Itk, Bmx, and Txk. Btk is essential for B-cell receptor signaling, because mutations in Btk are responsible for X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (xid) in mice, whereas Itk is involved in T-cell receptor signaling. Tec is expressed in both T and B cells, but its role in antigen receptor signaling is not clear. In this study, we show that Tec protein is expressed at substantially lower levels in primary T and B cells relative to Itk and Btk, respectively. However, Tec is up-regulated upon T-cell activation and in Th1 and Th2 cells. In functional experiments that mimic Tec up-regulation, we find that Tec overexpression in lymphocyte cell lines is sufficient to induce phospholipase Cgamma (PLC-gamma) phosphorylation and NFAT (nuclear factor of activated T cells) activation. In contrast, overexpression of Btk, Itk, or Bmx does not induce NFAT activation. Tec-induced NFAT activation requires PLC-gamma, but not the adapters LAT, SLP-76, and BLNK, which are required for Btk and Itk to couple to PLC-gamma. Finally, we show that the unique effector function for Tec correlates with a unique subcellular localization. We hypothesize that Tec functions in activated and effector T lymphocytes to induce the expression of genes regulated by NFAT transcription factors.
Tec蛋白酪氨酸激酶是一个家族的创始成员，该家族包括Btk、Itk、Bmx和Txk。Btk对B细胞受体信号传导至关重要，因为Btk的突变导致人类的X连锁无丙种球蛋白血症（XLA）和小鼠的X连锁免疫缺陷（xid），而Itk参与T细胞受体信号传导。Tec在T细胞和B细胞中均有表达，但其在抗原受体信号传导中的作用尚不清楚。在本研究中，我们发现，相对于Itk和Btk，Tec蛋白在原代T细胞和B细胞中的表达水平分别显著降低。然而，Tec在T细胞活化时以及在Th1和Th2细胞中上调。在模拟Tec上调的功能实验中，我们发现在淋巴细胞系中过表达Tec足以诱导磷脂酶Cγ（PLC-γ）磷酸化和活化T细胞核因子（NFAT）活化。相比之下，过表达Btk、Itk或Bmx不会诱导NFAT活化。Tec诱导的NFAT活化需要PLC-γ，但不需要Btk和Itk与PLC-γ偶联所需的衔接蛋白LAT、SLP-76和BLNK。最后，我们表明Tec独特的效应器功能与独特的亚细胞定位相关。我们推测Tec在活化的效应T淋巴细胞中发挥作用，以诱导由NFAT转录因子调控的基因表达。
