Cyclin-dependent kinase-like 5 (CDKL5, also known as STK9) is a serine/threonine protein kinase originally identified in 1998 during a transcriptional mapping project of the human X chromosome. Thereafter, a mutation in CDKL5 was reported in individuals with the atypical Rett syndrome, a neurodevelopmental disorder, suggesting that CDKL5 plays an important regulatory role in neuronal function. The disease associated with CDKL5 mutation has recently been recognised as CDKL5 deficiency disorder (CDD) and has been distinguished from the Rett syndrome owing to its symptomatic manifestation. Because CDKL5 mutations identified in patients with CDD cause enzymatic loss of function, CDKL5 catalytic activity is likely strongly associated with the disease. Consequently, the exploration of CDKL5 substrate characteristics and regulatory mechanisms of its catalytic activity are important for identifying therapeutic target molecules and developing new treatment. In this review, we summarise recent findings on the phosphorylation of CDKL5 substrates and the mechanisms of CDKL5 phosphorylation and dephosphorylation. We also discuss the relationship between changes in the phosphorylation signalling pathways and the Cdkl5 knockout mouse phenotype and consider future prospects for the treatment of mental and neurological disease associated with CDKL5 mutations.

中文翻译：

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细胞周期蛋白依赖性激酶样5（CDKL5）：可能的细胞信号转导靶点和CDKL5缺乏症的参与。

细胞周期蛋白依赖性激酶样5（CDKL5，也称为STK9）是一种丝氨酸/苏氨酸蛋白激酶，最初于1998年在人类X染色体的转录图谱计划中鉴定出。此后，在患有非典型Rett综合征（一种神经发育障碍）的个体中报告了CDKL5的突变，这表明CDKL5在神经元功能中起着重要的调节作用。最近，与CDKL5突变有关的疾病被认为是CDKL5缺乏症（CDD），由于其症状表现而与Rett综合征区分开来。因为CDKL5在CDD患者中鉴定出的突变会导致酶功能丧失，CDKL5的催化活性可能与该疾病密切相关。因此，探索CDKL5底物特性及其催化活性的调节机制对于鉴定治疗靶分子和开发新的治疗方法非常重要。在这篇综述中，我们总结了有关CDKL5底物磷酸化以及CDKL5磷酸化和去磷酸化机制的最新发现。我们还讨论了磷酸化信号通路的变化与Cdkl5基因敲除小鼠表型之间的关系，并考虑了与CDKL5突变相关的精神疾病和神经疾病的治疗方法。