Ceramide-1-phosphate: The “missing” link in eicosanoid biosynthesis and inflammation

A hypothetical mechanism of cPLA₂activation in response to the generation of C1P. The structure of cPLA₂α includes a CaLB/C2 domain (red and yellow), containing calcium binding regions (CBRs I, II and III; red), the PIP₂ domain (i.e., the catalytic domain; blue), and the hinge region (green). C1P has multiple roles in activating cPLA2α. Within the structure of cPLA₂α, Ser⁵⁰⁵ and Ser⁷²⁷ can be phosphorylated (blue spheres), by ERK, to activate cPLA₂α; C1P is shown as a direct activator of ERK as well as an indirect activator of ERK by inhibiting protein phosphatase 2A (PP2A). C1P also interacts directly with cPLA₂ near CBRII. Additionally, C1P increases calcium (Ca²⁺) concentrations, in a compartmentalized manner, in order to induce the association of cPLA₂α with perinuclear membranes. Sites of interaction with C1P and phosphatidylcholine (PC) are also indicated. See text for details.