CERKL is a homolog of the ceramide kinase (CERK) protein. Both proteins harbor a kinase domain related to the diacylglycerol kinases (DAGK) and a Pleckstrin homology (PH) domain. In addition, a C-terminal CERK-specific region is also present in CERKL.
11,12 Ceramide is the metabolic product of sphingolipids, which are part of the cell membrane, especially in neuronal cells. Generation of ceramide by hydrolysis of sphingolipids (e.g., sphingomyelin) is associated with the induction of apoptotic cell death and other stress-related responses.
13 Aberrant sphingolipid metabolism is associated with several neurodegenerative disorders; many of them, such as Tay-Sachs disease, Fabry's disease, and Neimann-Pick disease, are associated with blindness resulting from retinal degeneration.
14 Recent evidence suggests a strong correlation between sphingolipid signaling and survival and homeostasis of photoreceptor and retinal pigment epithelium cells.
15–17 The possibility that CERKL belongs to the CERK family and has a similar function was therefore very intriguing. However, various ceramides, known substrates for CERK and for other sphingolipids (including C8-, C2-, C6-, and C18-ceramide, dihydroceramide, phytoceramide, glucosylceramide, diacylglycerols, sphingosine, and complex sphingolipids such as sulfatides, cerebrosides, and gangliosides) were not phosphorylated by CERKL in vitro. Moreover, even using total lipid extracts from brain or kidney as a source of substrates, or providing the assay with crude tissue extracts to test for potential CERKL cofactors, did not stimulate CERKL activity.
11 Generation of
Cerkl-mutant mice did not help in clarifying the role of CERKL in the retina, as wild type (wt) levels of ceramide and ceramide-1-phosphate were found in the retinae of these mice.
18 Therefore, the kinase activity of CERKL remains questionable.