Spatial control of Ca2+ signals in lymphocytes

超出所提供的空间。淋巴细胞活化由多个细胞内信号传导过程组成。这种复杂性使得淋巴细胞能够以各种方式调节其功能，从而使其分化和活化得以正确进行。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最重要的转录因子之一。NF-AT由Ca 2 +/钙调蛋白依赖性磷酸酶钙调神经磷酸酶（CN）激活。NF-AT与CN的相互作用可被广泛用于抑制免疫反应的FK 506和环孢菌素A抑制。最近，一些细胞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，我们确定了一种蛋白Repsl，它结合淋巴特异性Src家族激酶Lck，并在淋巴细胞中的NF-AT活化中起关键作用。Repsl在胸腺细胞和其他淋巴器官中高度表达。鸡B细胞系DT-40中Repsl的基因敲除导致由于CN非依赖性途径的改变而废除NF-AT活化。即使当细胞被绕过近端信号事件的药理学试剂刺激时，NF-AT活化也没有恢复。此外，当被抗原受体刺激时，这些细胞比野生型细胞更易发生凋亡（抗原诱导的细胞死亡：AIDC）。 Reps 1与一种称为RalBP 1的蛋白质形成稳定的复合物，RalBP 1是一种小GTdR α 1的效应子，并对另一种GTdR α CDC 42/Rac蛋白具有GAP活性。显性负性形式的Ral的表达导致NF-AT的过度活化。此外，抗原受体诱导的细胞死亡显著增强。总之，Ral和Repsl对NF-AT调节具有相反的作用，但两者都抑制AIDC。在本研究中，我们将分析Repsl和Ral在淋巴细胞活化和死亡中的详细机制。性能现场=

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===========================================