Duan Lei, Reddi Alagarsamy Lakku, Ghosh Amiya, Dimri Manjari, Band Hamid
Division of Molecular Oncology, Department of Medicine, Evanston Northwestern Healthcare Research Institute, Feinberg School of Medicine, Northwestern University, IL 60201, USA.
Immunity. 2004 Jul;21(1):7-17. doi: 10.1016/j.immuni.2004.06.012.
Regulation of tyrosine kinase-mediated cellular activation through antigen receptors is of great biological and practical significance. The evolutionarily conserved Cbl family ubiquitin ligases have emerged as key negative regulators of activated tyrosine kinase-coupled receptors, and their impaired function switches a normal immune response into autoimmunity. Cbl proteins facilitate the ubiquitinylation of activated tyrosine kinases and other signaling proteins and of the signaling chains of receptors themselves; monoubiquitin tag promotes sorting of activated receptors and associated proteins into internal vesicles of the multivesicular body, facilitating their lysosomal degradation, whereas polyubiquitin tag promotes proteasomal degradation. Notably, increased expression of Cbl proteins and other ubiquitin ligases is a component of anergic signaling program in T cells. Thus, controlled destruction of the signaling apparatus has emerged as a key to fine-tuning antigen receptor signaling. Further studies of this pathway are likely to elucidate the pathogenesis of autoimmune diseases and offer new therapeutic targets.
通过抗原受体对酪氨酸激酶介导的细胞活化进行调控具有重大的生物学和实际意义。进化上保守的Cbl家族泛素连接酶已成为活化的酪氨酸激酶偶联受体的关键负调控因子，其功能受损会使正常免疫反应转变为自身免疫。Cbl蛋白促进活化的酪氨酸激酶和其他信号蛋白以及受体自身信号链的泛素化；单泛素标签促进活化受体和相关蛋白分选到多囊泡体的内部囊泡中，促进它们的溶酶体降解，而多泛素标签则促进蛋白酶体降解。值得注意的是，Cbl蛋白和其他泛素连接酶表达增加是T细胞无反应性信号程序的一个组成部分。因此，信号装置的受控破坏已成为微调抗原受体信号的关键。对该途径的进一步研究可能会阐明自身免疫性疾病的发病机制并提供新的治疗靶点。
