Cho Clifford S, Elkahwaji Johny, Chang Zheng, Scheunemann Tara L, Manthei Eric R, Hamawy Majed M
Department of Surgery, Division of Transplantation, University of Wisconsin, H4/749, CSC, 600 Highland Avenue, Madison, WI 53792, USA.
Cell Signal. 2003 Jan;15(1):85-93. doi: 10.1016/s0898-6568(02)00046-3.
The linker for activation of T cells (LAT) is essential for T cell activation. Cyclosporin A (CsA) and FK506, inhibitors of T cell proliferation, have been very useful for preventing autoimmune and inflammatory disease and graft rejection. However, both compounds are associated with side effects. We show that TCR ligation in the presence of FK506 or CsA induced rapid modifications in LAT that modulate the electrophoretic mobility of the molecule in SDS-PAGE. Calcineurin, a target for CsA and FK506, dephosphorylated LAT in vitro and restored its electrophoretic mobility. Stimulating T cells with the protein kinase C (PKC) activator PMA induced a shift in the mobility of LAT, whereas inhibitors of PKC blocked the effect of PMA. Thus, manipulating calcineurin or PKC activation alters the electrophoretic mobility of LAT. These results shed light on the molecular actions of CsA and FK506 in T cells and implicate LAT in mediating the drugs' actions.
T细胞活化连接蛋白（LAT）对于T细胞活化至关重要。环孢素A（CsA）和FK506是T细胞增殖抑制剂，在预防自身免疫性疾病、炎症性疾病和移植排斥反应方面非常有用。然而，这两种化合物都有副作用。我们发现，在FK506或CsA存在的情况下，TCR连接会诱导LAT发生快速修饰，从而调节该分子在SDS-PAGE中的电泳迁移率。钙调神经磷酸酶是CsA和FK506的作用靶点，它在体外使LAT去磷酸化并恢复其电泳迁移率。用蛋白激酶C（PKC）激活剂佛波酯（PMA）刺激T细胞会导致LAT迁移率发生改变，而PKC抑制剂则会阻断PMA的作用。因此，操纵钙调神经磷酸酶或PKC活化会改变LAT的电泳迁移率。这些结果揭示了CsA和FK506在T细胞中的分子作用，并表明LAT参与介导药物的作用。
