Abstract
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.
Highlights
Protein phosphorylation is a chemical modification that plays a crucial role in many pivotal biological processes, including cell division, differentiation, and higher-order neural function
Mutations in Cyclin-dependent kinase-like 5 (CDKL5) and forkhead box protein G1 (FOXG1) have resulted in unique diseases that are distinguishable from the Rett syndrome, since the specific symptoms of the disease vary depending on the causative gene involved [12,13,14]
Other kinases that function to CDKL5 include Ca2+/calmodulin-dependent protein kinase II (CaMKII), which preferentially recognises an Arg residue at the P–3 position [79, 80]; mitogen-activated protein kinase (MAPK), which preferentially recognises a Pro residue at the P–2 position [80, 81]; and dualspecificity tyrosine phosphorylation-regulated kinase 1a (Dyrk1a), which possesses both of the above specificities [82]
Summary
Protein phosphorylation is a chemical modification that plays a crucial role in many pivotal biological processes, including cell division, differentiation, and higher-order neural function. Mutations in CDKL5 and FOXG1 have resulted in unique diseases that are distinguishable from the Rett syndrome, since the specific symptoms of the disease vary depending on the causative gene involved [12,13,14]. CDKL5 (STK9) was first reported in 1998 as a gene encoding a novel protein kinase situated on the X chromosome. It was discovered during a transcriptional mapping project [19]. Nonsense mutations completely inhibit the ability of CDKL5 to interact with proteins that typically interact with its C-terminus These observations illustrate the possible mechanisms of the involvement of nonsense mutations in disease onset. We will outline the major findings of CDKL5 research and discuss possible future developments
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
