Regulation of TNF and SFK signalling in immune cells by TCPTP

肿瘤坏死因子（TNF）是一种强有力的促炎细胞因子，在免疫和炎症中起重要作用。TNF作用于细胞表面以激活两个关键的细胞通信或信号传导途径：促分裂原活化蛋白激酶（MAPK）途径和核因子κ B（NF κ B）途径。这两种途径的相对激活可以决定细胞是否存活和增殖或分化或以其他方式响应TNF而死亡，因此决定免疫或炎症反应的性质。已知T细胞蛋白酪氨酸磷酸酶（TCPTP）在免疫系统中是重要的，并且充当炎症的负调节剂。我们的初步研究已经确定TCPTP作为选择性调节TNF诱导的MAPK，但不是NF κ B信号。TCPTP通过灭活Src家族激酶（SFK）发挥其作用，而Src家族激酶本身是免疫和炎症反应的组成部分。在本提案中，我们将阐明TCPTP在TNF信号传导中功能的分子基础，并表征TCPTP在免疫细胞（特别是T细胞）中TNF和SFK功能中的作用。

Tumour necrosis factor (TNF) is a potent proinflammatory cytokine that plays an important role in immunity and inflammation. TNF acts on the cell surface to activate two key cellular communication or signalling pathways: the mitogen-activated protein kinase (MAPK) pathway and the nuclear factor kappaB (NFkappaB) pathway. The relative activation of the two pathways can dictate whether cells live and proliferate or differentiate or otherwise die in response to TNF, and therefore determine the nature of the immune or inflammatory response. The T-cell protein tyrosine phosphatase (TCPTP) is known to be important in the immune system and serves as a negative regulator of inflammation. Our preliminary studies have identified TCPTP as a selective regulator of TNF-induced MAPK but not NFkappaB signaling. TCPTP exerts its effects by inactivating Src family kinases (SFK) which are themselves integral to immune and inflammatory responses. In this proposal we will elucidate the molecular basis for TCPTP function in TNF- signalling and characterise the role of TCPTP in TNF and SFK functions in immune cells, in particular T-cells.