Roskoski Robert
Blue Ridge Institute for Medical Research, 3754 Brevard Road, Suite 106, Box 19, Horse Shoe, NC 28742, United States.
Pharmacol Res. 2022 Sep;183:106362. doi: 10.1016/j.phrs.2022.106362. Epub 2022 Jul 22.
The Janus kinase (JAK) family of nonreceptor protein-tyrosine kinases consists of JAK1, JAK2, JAK3, and TYK2 (Tyrosine Kinase 2). Each of these proteins contains a JAK homology pseudokinase (JH2) domain that interacts with and regulates the activity of the adjacent protein kinase domain (JH1). The Janus kinase family is regulated by numerous cytokines including interferons, interleukins, and hormones such as erythropoietin and thrombopoietin. Ligand binding to cytokine receptors leads to the activation of associated Janus kinases, which then catalyze the phosphorylation of the receptors. The SH2 domain of signal transducers and activators of transcription (STAT) binds to the cytokine receptor phosphotyrosines thereby promoting STAT phosphorylation and activation by the Janus kinases. STAT dimers are then translocated into the nucleus where they participate in the regulation and expression of dozens of proteins. JAK1/3 signaling participates in the pathogenesis of inflammatory disorders while JAK1/2 signaling contributes to the development of myeloproliferative neoplasms as well as several malignancies including leukemias and lymphomas. An activating JAK2 V617F mutation occurs in 95% of people with polycythemia vera and about 50% of cases of myelofibrosis and essential thrombocythemia. Abrocitinib, ruxolitinib, and upadacitinib are JAK inhibitors that are FDA-approved for the treatment of atopic dermatitis. Baricitinib is used for the treatment of rheumatoid arthritis and covid 19. Tofacitinib and upadacitinib are JAK antagonists that are used for the treatment of rheumatoid arthritis and ulcerative colitis. Additionally, ruxolitinib is approved for the treatment of polycythemia vera while fedratinib, pacritinib, and ruxolitinib are approved for the treatment of myelofibrosis.
非受体蛋白酪氨酸激酶的 Janus 激酶（JAK）家族由 JAK1、JAK2、JAK3 和 TYK2（酪氨酸激酶 2）组成。这些蛋白质中的每一种都包含一个 JAK 同源假激酶（JH2）结构域，该结构域与相邻的蛋白激酶结构域（JH1）相互作用并调节其活性。Janus 激酶家族受多种细胞因子调节，包括干扰素、白细胞介素以及促红细胞生成素和血小板生成素等激素。配体与细胞因子受体结合会导致相关 Janus 激酶的激活，然后 Janus 激酶催化受体的磷酸化。信号转导和转录激活因子（STAT）的 SH2 结构域与细胞因子受体磷酸酪氨酸结合，从而促进 STAT 被 Janus 激酶磷酸化和激活。然后 STAT 二聚体转移到细胞核中，在那里它们参与数十种蛋白质的调节和表达。JAK1/3 信号传导参与炎症性疾病的发病机制，而 JAK1/2 信号传导则促进骨髓增殖性肿瘤以及包括白血病和淋巴瘤在内的多种恶性肿瘤的发展。95%的真性红细胞增多症患者以及约 50%的骨髓纤维化和原发性血小板增多症患者会出现激活型 JAK2 V617F 突变。阿布昔替尼、鲁索替尼和乌帕替尼是美国食品药品监督管理局（FDA）批准用于治疗特应性皮炎的 JAK 抑制剂。巴瑞替尼用于治疗类风湿性关节炎和新冠病毒 19。托法替布和乌帕替尼是用于治疗类风湿性关节炎和溃疡性结肠炎的 JAK 拮抗剂。此外，鲁索替尼被批准用于治疗真性红细胞增多症，而费德拉替尼、帕西替尼和鲁索替尼被批准用于治疗骨髓纤维化。
