Recent advances in the molecular mechanism of Janus kinase activation

The JAK (Janus kinase) family members play a role in the transmission of signals from extracellular stimuli across the plasma membrane via the cytoplasm to the nucleus in eukaryotes. The JAK family is comprised of JAK1, JAK2, JAK3 and TYK2 (tyrosine kinase 2), and the complexities underlying their activation and regulation are still being investigated. Here, we review the recent advances of their functions and the underlying mechanism of activation. At the molecular level, recent studies have greatly advanced our knowledge of the structures and organization of the JAK proteins, as well as the mechanism of JAK activation, particularly the role of the pseudokinase domain as a suppressor of the adjacent tyrosine kinase domain’s catalytic activity. We also review recent advances in our understanding of the mechanisms of negative regulation exerted by phosphatase and SH2 (Src homology 2) domain-containing proteins. These recent studies highlight the diversity of regulatory mechanisms utilized by the JAK family to maintain signalling fidelity, and shed much light on the potential novel strategies for precise treatment of the associated diseases.

脓毒血症性急性肾损伤的发生机制

目的探讨脓毒血症性急性肾损伤(AKI)的发生机制。方法将雄性成年大鼠32只随机分为模型组(n=16)与正常组(n=16),模型组腹腔注射脂多糖(LPS)20 mg/kg建立脓毒血症模型,正常组给予等量生理盐水。在建模后1、24和48 h,比较两组血清白介素-1β(IL-1β)和肿瘤坏死因子-α(TNF-α)、肾功能相关指标、Tec非受体型激酶、肾小管自噬及凋亡标志蛋白微管相关蛋白1(Beclin-1)、轻链3-Ⅱ(LC3-Ⅱ)水平的变化。结果与正常组相比,建模后1 h,模型组血BUN无明显变化,而CysC明显升高(P <0.05),肾脏组织出现轻度损伤;建模后24 h,大鼠肾功能指标均显著升高。建模后1 h,大鼠血清IL-1β和TNF-ɑ水平显著提升,在24 h时升高最明显。与正常组比较,建模后各个时间点,模型组肾小管细胞Tec非受体激酶及LC3-Ⅱ及Beclin-1的蛋白表达均明显升高,尤其在建模24 h最明显(P <0.05);建模后48 h有所降低,但仍明显高于正常组(P <0.05)。结论 Tec非受体激酶可能参与脓毒血症AKI的早期发病,并可能通过参与免疫途径调节细胞自噬和凋亡的机制而发挥作用。