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Targeted Deletion of Protein Kinase C Reveals a Distribution of Functions between the Two Atypical Protein Kinase C Isoforms¹

Rachel S. Soloff^2,*,, Carol Katayama^*,, Meei Yun Lin^*,, James R. Feramisco^,, and Stephen M. Hedrick^3,*,,¶

^* Division of Biological Sciences, Moores University of California at San Diego Cancer Center, Department of Medicine, Department of Pharmacology, and ^¶ Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093

Protein kinase C (PKC) is an atypical member of the PKC family of serine/threonine kinases with high similarity to the other atypical family member, PKC. This similarity has made it difficult to determine specific roles for the individual atypical isoforms. Both PKC and PKC have been implicated in the signal transduction, initiated by mediators of innate immunity, that culminates in the activation of MAPKs and NF-B. In addition, work from invertebrates shows that atypical PKC molecules play a role in embryo development and cell polarity. To determine the unique functions of PKC, mice deficient for PKC were generated by gene targeting. The ablation of PKC results in abnormalities early in gestation with lethality occurring by embryonic day 9. The role of PKC in cytokine-mediated cellular activation was studied by making mouse chimeras from PKC-deficient embryonic stem cells and C57BL/6 or Rag2-deficient blastocysts. Cell lines derived from these chimeric animals were then used to dissect the role of PKC in cytokine responses. Although the mutant cells exhibited alterations in actin stress fibers and focal adhesions, no other phenotypic differences were noted. Contrary to experiments using dominant interfering forms of PKC, mutant cells responded normally to TNF, serum, epidermal growth factor, IL-1, and LPS. In addition, no abnormalities were found in T cell development or T cell activation. These data establish that, in vertebrates, the two disparate functions of atypical PKC molecules have been segregated such that PKC mediates signal transduction of the innate immune system and PKC is essential for early embryogenesis.

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