The linoleic acid derivative 8-[2-(2-pentyl-cyclopropylmethyl)-cyclopropyl]-octanoic acid (DCP-LA), with cyclopropane rings instead of cis-double bonds, serves as a selective activator of PKCε. The present study investigated whether PKCε, activated by DCP-LA, phosphorylates PKCε itself and how phosphorylated PKCε affects its own activity. DCP-LA phosphorylated PKCε at the serine residues, but not the threonine residues, in PC-12 cells, which is abolished the PKC inhibitor GF109203X. The plasmids for wild-type and mutant PKCε were transfected into MSTO-211H human malignant mesothelioma cells with very little expression of the PKCε mRNA. DCP-LA enhanced PKCε activity approximately 7 folds in MSTO-211H cells transfected with the wild-type rat PKCε plasmid as compared with that in non-transfected control cells. Such effect was not obtained with cells transfected with the plasmid for mutant rat PKCε replacing Ser234, Ser316, Ser368, or Ser729 by Ala. Taken together, these results indicate that PKCε, activated by DCP-LA, enhances its own activity through serine autophosphorylation