Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Avda. Menéndez Pidal s/n., 14004, Córdoba, Spain.
Departamento de Biología Celular, Fisiología E Inmunología, Universidad de Córdoba, Córdoba, Spain.
Cell Mol Life Sci. 2020 Dec;77(23):4747-4763. doi: 10.1007/s00018-020-03556-1. Epub 2020 May 27.
Members of the dual-specificity tyrosine-regulated kinase (DYRKs) subfamily possess a distinctive capacity to phosphorylate tyrosine, serine, and threonine residues. Among the DYRK class II members, DYRK2 is considered a unique protein due to its role in disease. According to the post-transcriptional and post-translational modifications, DYRK2 expression greatly differs among human tissues. Regarding its mechanism of action, this kinase performs direct phosphorylation on its substrates or acts as a priming kinase, enabling subsequent substrate phosphorylation by GSK3β. Moreover, DYRK2 acts as a scaffold for the EDVP E3 ligase complex during the G2/M phase of cell cycle. DYRK2 functions such as cell survival, cell development, cell differentiation, proteasome regulation, and microtubules were studied in complete detail in this review. We have also gathered available information from different bioinformatic resources to show DYRK2 interactome, normal and tumoral tissue expression, and recurrent cancer mutations. Then, here we present an innovative approach to clarify DYRK2 functionality and importance. DYRK2 roles in diseases have been studied in detail, highlighting this kinase as a key protein in cancer development. First, DYRK2 regulation of c-Jun, c-Myc, Rpt3, TERT, and katanin p60 reveals the implication of this kinase in cell-cycle-mediated cancer development. Additionally, depletion of this kinase correlated with reduced apoptosis, with consequences on cancer patient response to chemotherapy. Other functions like cancer stem cell formation and epithelial-mesenchymal transition regulation are also controlled by DYRK2. Furthermore, the pharmacological modulation of this protein by different inhibitors (harmine, curcumine, LDN192960, and ID-8) has enabled to clarify DYRK2 functionality.
双特异性酪氨酸调节激酶 (DYRKs) 亚家族的成员具有独特的磷酸化酪氨酸、丝氨酸和苏氨酸残基的能力。在 DYRK 类 II 成员中，DYRK2 因其在疾病中的作用而被认为是一种独特的蛋白质。根据转录后和翻译后修饰，DYRK2 在人体组织中的表达差异很大。就其作用机制而言，这种激酶对其底物进行直接磷酸化，或作为启动激酶，使 GSK3β 随后对底物进行磷酸化。此外，DYRK2 在细胞周期的 G2/M 期作为 EDVP E3 连接酶复合物的支架。在本综述中，详细研究了 DYRK2 的细胞存活、细胞发育、细胞分化、蛋白酶体调节和微管等功能。我们还从不同的生物信息资源中收集了可用信息，以显示 DYRK2 相互作用组、正常和肿瘤组织表达以及复发性癌症突变。然后，在这里我们提出了一种创新的方法来阐明 DYRK2 的功能和重要性。已经详细研究了 DYRK2 在疾病中的作用，突出了这种激酶在癌症发展中的关键作用。首先，DYRK2 对 c-Jun、c-Myc、Rpt3、TERT 和 katanin p60 的调节揭示了该激酶在细胞周期介导的癌症发展中的作用。此外，该激酶的耗竭与细胞凋亡减少相关，这对癌症患者对化疗的反应有影响。其他功能，如癌症干细胞形成和上皮-间充质转化的调节，也受 DYRK2 控制。此外，通过不同抑制剂（哈梅林、姜黄素、LDN192960 和 ID-8）对该蛋白进行药理学调节，使 DYRK2 的功能得以阐明。
