Protein kinase C (PKC) family members regulate numerous cellular responses including gene expression, protein secretion, cell proliferation, and the inflammatory response. The basic protein structure includes an N-terminal regulatory region connected to a C-terminal kinase domain by a hinge region. PKC enzymes contain an auto-inhibitory pseudosubstrate domain that binds a catalytic domain sequence to inhibit kinase activity.

Protein Kinase C and Cancer

PKC is a family of serine threonine kinases that play a major role in cell signaling and a variety of cellular processes including proliferation, differentiation, cell motility, and apoptosis. The PKC family is comprised of at least 12 isoforms with distinct cellular functions that are divided into three subgroups: the classical PKCs (PKCα, β1, PKCβ2, and PKCγ) that are activated by Ca2+ and DAG, the novel PKCs (PKCδ, PKCε, PKCθ and PKCη) that are only activated by DAG, and the atypical PKCs (PKCζ and PKCι) that do not respond to either Ca2+ or DAG. The findings that PKC acts as a high-affinity intracellular receptor for the tumor promoter phorbol esters indicated an important role for PKC in carcinogenesis and positioned it as an important molecular therapeutic target in cancer. Indeed, the role of PKC in carcinogenesis and as a potential target in cancer therapy has been studied in various cellular systems, and the results of these studies are summarized in a large number of reviews. The role of PKC in cancer is not due to mutations in PKC genes and other than rare mutations in PKCα, there have been no reports of mutations in other PKC isoforms. Therefore it seems that the contribution of a specific PKC isoform to carcinogenesis may result from aberrant expression, enhanced activation downstream to growth factors receptors, and changes in subcellular localization or depletion as a result of prolonged activation. In addition, the interaction of PKC isoforms with different oncogenes or tumor suppressors may also impact their contribution to carcinogenesis.

PKCs in Lymphocyte Disorders

Members of the PKC family of Ser/Thr kinases have been implicated in aberrant signaling responses contributing towards malignant transformation, based upon the fact that they are cellular receptors for tumor promoting phorbol esters, shown to protect various cells, including T cells, from apoptosis. Due to this potentially transforming capacity of PKC family genes, high levels of PKC expression are expected to be involved in naturally occurring lymphocyte malignancies. Upregulated expression levels of distinct PKC isotypes in most tumor cell lines further argue for a functional link between PKC and oncogenesis. Recent studies have directly linked distinct PKC isotypes to molecular pathways regulating apoptosis.

Chronic membrane recruitment of the PKCθ (by an undefined mechanism) into the membrane fraction of the malignant cells has been reported in cell lines derived from patients suffering from T cell leukaemia. High levels of membrane-bound PKCθ in malignant cells implicate PKCθ in cellular mechanisms regulating the sustained proliferation of T cells, however, it would be very important to learn whether this subcellular translocation of PKCθ in tumor cells also correlates with increased enzymatic activation of PKCθ. Other more definitive results demonstrate that both Bcr-Abl and PKCι activity are necessary for apoptotic resistance in hematopoietic K562 cells, supporting a functional role for PKCι in leukemia cell survival. Theoretically, as mechanism, PKC family genes may also be directly involve in accidental recombination during intrachromosomal rearrangement or even interchromosomal translocations, similarly to the deleterious joining of abl sequences to the immunoglobulin or bcr loci leading to a malignancy. However no clinical example of a causative role of PKCs in primary T cell malignancy has been published so far.

Gain-of-function mutants in PKCs in T cells may not only result in malignant T cell transformation but also result in hyper-responsiveness to antigen stimulation and thereby to the exaggerated immune responses that seem to characterize many autoimmune but also inflammatory diseases. Consistently, reduced or absent immune responses may be caused by (point)mutation for instance in the PKCθ gene, potentially resulting in reduced levels or loss-of-function and consequently in immunodeficiency.

Even though no clinical cases have been reported, genetic dissection of the naturally occurring human familial immunodeficiencies, and malignant somatic cell mutants, may be crucial to our understanding of the entire molecular framework of PKCs and how PKCs coordinate their actions to promote biological responses in humans. Together with biochemical information from studies on signal transduction and the phenotype of the PKC KO-mice, genetic studies in well defined groups of human patients in search for PKC genetic defects/abnormalities associated with distinct genetic syndromes will illuminate if, and eventually how, PKCs are involved in such kind of genetic disease.


Toker, A. (2010). Protein Kinase C in Cancer Signaling and Therapy: Introduction and Historical Perspective. In Protein Kinase C in Cancer Signaling and Therapy (pp. 3-8). Humana Press, Totowa, NJ.

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