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

Abstract

Protein kinase C λ (PKCλ) is an atypical member of the PKC family of serine/threonine kinases with high similarity to the other atypical family member, PKCζ. This similarity has made it difficult to determine specific roles for the individual atypical isoforms. Both PKCλ and PKCζ have been implicated in the signal transduction, initiated by mediators of innate immunity, that culminates in the activation of MAPKs and NF-κB. 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 PKCλ, mice deficient for PKCλ were generated by gene targeting. The ablation of PKCλ results in abnormalities early in gestation with lethality occurring by embryonic day 9. The role of PKCλ in cytokine-mediated cellular activation was studied by making mouse chimeras from PKCλ-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 PKCλ 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 PKCλ, 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 PKCζ mediates signal transduction of the innate immune system and PKCλ is essential for early embryogenesis.

Regulation of glioblastoma cell invasion by PKCι and RhoB

“…The actin cytoskeleton is a dynamic element within cells that undergoes changes that are essential to cell motility (Lambrechts et al, 2004). PKCi depletion resulted in the formation of long actin stress fibers; similar changes in stress fibers were described by Soloff et al (2004), in PKCi knockout mouse embryonic fibroblasts) and other studies have also implicated the atypical protein kinase C family in stress fiber loss (Uberall et al, 1999;Coghlan et al, 2000).…”

Surfactant Protein A Activation of Atypical Protein Kinase C ζ in IκB-α-Dependent Anti-Inflammatory Immune Regulation

“…Whereas PKC / Ϫ/Ϫ mice are embryonic lethal (46), PKC Ϫ/Ϫ mice are grossly normal, but exhibit an impairment of IKK activation in whole lung extracts after LPS challenge (33). In freshly isolated AM from PKC Ϫ/Ϫ mice, however, NF-B activation was apparent both basal and LPS induced.…”

Analysis of aPKCλ and aPKCζ reveals multiple and redundant functions during vertebrate retinogenesis

“…Genetic deletion studies in mice have demonstrated an essential role for aPKCλ during early mammalian embryogenesis, as all aPKCλ -/-mice are embryonic lethal (Soloff et al, 2004). Homozygous aPKCζ -/-mice, however, show normal embryogenesis, suggesting that aPKCλ may compensate for loss of aPKCζ within those embryos (Leitges et al, 2001).…”