Li Quan, Ren Jian, Kufe Donald
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02482, USA.
Biochem Biophys Res Commun. 2004 Mar 5;315(2):471-6. doi: 10.1016/j.bbrc.2004.01.075.
The MUC1 transmembrane glycoprotein is aberrantly expressed by diverse hematologic malignancies, including those of the T cell lineage. The MUC1 cytoplasmic domain (CD) interacts with beta-catenin; however, the role of MUC1 in T cells is not known. In the present work, MUC1 was studied as a potential downstream effector of the Lck and ZAP-70 tyrosine kinases that are essential for T cell activation. The results demonstrate that anti-CD3-induced or PMA+ionomycin-induced activation of Jurkat T cells is associated with increased binding of MUC1 and Lck. Lck phosphorylates MUC1-CD on Y-46 and, in turn, stimulates the binding of MUC1 to beta-catenin. The results further demonstrate that MUC1 interacts with ZAP-70. In contrast to Lck, ZAP-70 phosphorylates MUC1-CD predominantly on Y-20. However, like Lck, ZAP-70-mediated phosphorylation of MUC1 Y-20 stimulates binding of MUC1 and beta-catenin. These findings indicate that MUC1 functions as a substrate for Lck and ZAP-70 in activated Jurkat T cells and that MUC1 integrates T cell receptor signaling with the beta-catenin pathway.
MUC1跨膜糖蛋白在多种血液系统恶性肿瘤中异常表达，包括T细胞系恶性肿瘤。MUC1胞质结构域（CD）与β-连环蛋白相互作用；然而，MUC1在T细胞中的作用尚不清楚。在本研究中，MUC1作为Lck和ZAP-70酪氨酸激酶的潜在下游效应物进行了研究，这两种激酶对T细胞活化至关重要。结果表明，抗CD3诱导或佛波酯+离子霉素诱导的Jurkat T细胞活化与MUC1和Lck结合增加有关。Lck使MUC1-CD的Y-46位点磷酸化，进而刺激MUC1与β-连环蛋白的结合。结果进一步表明，MUC1与ZAP-70相互作用。与Lck不同，ZAP-70主要使MUC1-CD的Y-20位点磷酸化。然而，与Lck一样，ZAP-70介导的MUC1 Y-20位点磷酸化刺激MUC1与β-连环蛋白的结合。这些发现表明，MUC1在活化的Jurkat T细胞中作为Lck和ZAP-70的底物发挥作用，并且MUC1将T细胞受体信号与β-连环蛋白途径整合在一起。
