Schematic representation of LPS-mediated signal transduction pathways leading to JNK activation—a working model.

LPS-stimulated tyrosine kinase(s) activate PI 3-K, which in turn generates the phosphoinositides PI(3,4)P2 and PI(3,4,5)P3. Activation of the downstream target PKCζ occurs through PDK1-mediated phosphorylation of T410 in the C-loop of PKCζ. The possibility of an allosteric activation of PKCζ by PI(3,4)P2, PI(3,4,5)P3, or both is indicated by a dotted arrow. PKCζ stimulates PC-PLC, which generates DAG required for the activation of ASMase. This in turn results in the production of the second messenger ceramide and in SEK/JNK activation. A candidate link between PC-PLC/ASMase pathway and SEK/JNK module is TAK1, a ceramide-stimulative SEK1 kinase. Speculative steps are indicated by question marks, and possible feedback mechanisms are depicted by dotted lines.