The role of ceramide-1-phosphate in biological functions

Abstract

In mammalian cells, cermide-1-phosphate (C1P) is produced via the ATP-dependent mechanism of converting ceramide to C1P by the enzyme, ceramide kinase (CERK). CERK was first described as a calcium-stimulated lipid kinase that co-purified with brain synaptic vesicles, and to date, CERK is the only identified mammalian enzyme known to produce C1P in cells. C1P has steadily emerged as a bioactive sphingolipid involved in cell proliferation, macrophage migration, and inflammatory events. The recent generation of the CERK knockout mouse and the development of CERK inhibitors have furthered our current understanding of CERK-derived C1P in regulating biological processes. In this chapter, the history of C1P as well as the biological functions attributed to C1P are reviewed.

Fig. 1

The interaction between C1P and cPLA₂α is a crucial link in eicosanoid synthesis. Following an inflammatory stimulus, Ca²⁺ activated cPLA₂α translocates to the golgi membrane where it binds phosphatidylcholine (PC). CERK-derived C1P directly interacts with cPLA₂α, thereby enhancing the association of cPLAα to the PC-rich membrane. cPLA₂α hydrolyzes PC to produce arachidonic acid (AA), which is further metabolized to several different eicosanoids, one of which is prostaglandin (PGH₂). Prostaglandins are involved in various biological processes associated with the inflammatory response

Fig. 2

Prospective role of C1P in TNFα production via direct inhibition of TACE. ADAM17/ TACE is the major metalloprotease responsible for cleaving or “shedding” mature TNFα (pro-TNFα) to release the active soluble form. Recent studies have demonstrated a direct interaction between C1P and TACE, which inhibits the sheddase activity and hinders the ability of TACE to release active TNFα. Current investigations are focused on identifying the TACE residues that mediate the interaction of the enzyme with C1P