Hum Mol Genet. 2005 Dec 5; [Epub ahead of print]
CDKL5/Stk9 Kinase Inactivation is Associated with Neuronal Developmental Disorders
Lin C, Franco B, Rosner MR.
Department of Neurobiology, Pharmacology and Physiology, University of Chicago, Chicago, IL 60637; Ben May Institute for Cancer Research, Center for Integrative Sciences (CIS), University of Chicago, 929 East 57 Street, Chicago, IL 60637.
Abstract
X-linked cyclin-dependent kinase-like 5 (CDKL5 or STK9) has recently been implicated in atypical Rett and X-linked West Syndromes, severe neurological disorders associated with mental retardation, loss of communication and motor skills, and infantile spasms and seizures in predominantly females. Besides CDKL5 these disease phenotypes are also linked to mutations in the MECP2 and ARX genes. Here, we have expressed and characterized CDKL5 and its mutant forms. CDKL5 is a 118 kDa protein that is widely distributed in all tissues, with highest levels in brain, thymus, and testes. Whole mount embryo staining reveals CDKL5 to be ubiquitous. Within cells, CDKL5 is localized primarily in the nucleus. Removal of the C-terminal domain increases CDKL5 expression, enhances autophosphorylation activity, and causes perinuclear localization, indicating that the C-terminus regulates CDKL5 function. Although we detect MeCP2 but not ARX binding to CDKL5, our results suggest that neither of these proteins are direct substrates of the CDKL5 kinase. Finally, the CDKL5 mutations associated with the disease phenotype cause loss of kinase activity as assessed by autophosphorylation. These results suggest that inactivation of the CDKL5 kinase can lead to severe neurodevelopmental disorders.
Lay Summary
The performance of a car's engine can be greatly modified by the addition of after-market parts. Similarly, the function of a single protein within a cell can be greatly modified by the addition of molecules; most notably, a "phosphate group". Many enzymes, receptors, and other proteins are turned "on" or "off" respectively by phosphorylation (the addition of a phosphate group by a "kinase") and de-phosphorylation (the remove of a phosphate group by a "phosphotase"). Indeed, the roles of kinases and phosphotases have been a hot area of research throughout many fields of medicine and biology. Recently, one kinase in particular - X-linked cyclin-dependent kinase-like 5 (CDKL5 or STK9) - has been suggested to play a role in the development of atypical Rett Syndrome. However, very little is known about CDKL5. In this paper, the authors shed light on this uncertainty by discussing its location, function, and activity. Predictably, mutations in CDKL5 lead to decreases in phosphorylation activity. Interestingly, although expressed in the same cells as MeCP2, the results suggest that CDKL5 is not a main kinase for MeCP2. This is somewhat not unexpected, as the inactivation of CDKL5 leads to developmental consequences greater than atypical Rett Syndrome alone. Nonetheless, this is an important paper which sheds light into the mechanisms underlying atypical Rett Syndrome.