Spatial control of Ca2+ signals in lymphocytes

超出提供的空间。I淋巴细胞的激活包括多个细胞内信号传递过程。这种复杂性允许淋巴细胞以各种方式调节自己的功能，以便正确地进行分化和激活。这一复杂系统的损伤可能导致免疫系统功能障碍，如自身免疫、过敏和免疫缺陷。活化T细胞核因子(NF-AT)被认为是控制淋巴细胞活化的重要转录因子之一。核因子-AT由钙/钙调蛋白依赖的磷酸酶钙调神经磷酸酶(CN)激活。FK506和环孢菌素A可抑制NF-AT和CN之间的相互作用，这两种药物被广泛用于抑制免疫反应。最近，几种细胞蛋白和病毒蛋白也被确定为CN/NF-AT相互作用的抑制剂。在初步研究中，我们鉴定了一种蛋白Repsl，它与淋巴特异性的Src家族激酶Lck结合，并在淋巴细胞中的NF-AT激活中发挥关键作用。Reps1在胸腺细胞和其他淋巴器官中高表达。鸡B细胞系DT-40中的Reps1基因敲除后，由于CN非依赖途径的改变，导致了NF-AT激活的取消。即使在绕过近端信号转导事件的药物刺激下，核因子-AT的激活也不能恢复。此外，当抗原受体刺激时，这些细胞比野生型细胞更容易发生凋亡(抗原诱导的细胞死亡：AIDC)。REPS 1与一种名为RalBP1的蛋白质形成稳定的复合体，RalBP1是小GTP酶Ral的效应器，对另一种GTP酶CDc42/Rac蛋白具有间隙活性。显性负性RAL的表达导致了核因子-AT的过度激活。此外，抗原受体诱导的细胞死亡明显增强。Ral和Reps1对NF-AT的调节作用相反，但对AIDC均有抑制作用。在本研究中，我们将分析Reps1和Ral功能在淋巴细胞激活和死亡中的详细机制。表演网站========================================Section End===========================================

EXCEED THE SPACE PROVIDED. I Lymphocyte activation consists of multiple intra-cellular signaling processes. This complexity allows lymphocytes to regulate their function in various ways so that their differentiation and activation are properly carried out. Impairment in this complex system could lead to malfunctioning of the immune system, such as autoimmunity, allergy, and immunodeficiency. Nuclear factor of activated T-cells (NF-AT) is regarded as one of the most important transcription factors that controls lymphocyte activation. NF-AT is activated by Ca2+/calmodulin-dependent phosphatase calcineurin (CN). The interaction between NF-AT and CN is inhibited by FK506 and Cyclosporin A, which are broadly utilized for suppression of the immune responses. Recently, several cellular and viral proteins were also determined as the inhibitors of CN/NF-AT interaction. In the preliminary study, we identify a protein Repslthat binds the lymphoid specific Src family kinase Lck and plays a critical role in NF-AT activation in lymphocytes. Repsl is highly expressed in thymocytes and other lymphoid organs. Gene knockout of Repsl in a chicken B-cell line DT-40 resulted in abolishment of NF-AT activation due to alterations in the CN independent pathway. NF-AT activation was not restored even when cells were stimulated by pharmacological agents that bypass proximal signaling events. Additionally, these cells are more susceptible to apoptosis (antigen induced cell death:AIDC) than the wildtype cells when stimulated by the antigen receptor. Reps 1 forms a stable complex with a protein called RalBP1, which is an effector for a small GTPase Ral and has GAP activity for another GTPase CDC42/Rac proteins. Expression of a dominant negative form of Ral resulted in hyper-activation of NF-AT. Moreover, antigen receptor induced cell death was significantly enhanced. Together, Ral and Repsl have opposite effects on NF-AT regulation but both are suppressive to AIDC. In this study, we will analyze the detailed mechanism of Repsl and Ral function in lymphocyte activation and death. PERFORMANCE SITE ========================================Section End===========================================