Protein kinase Cepsilon makes the life and death decision

Abstract

Cancer is caused by dysregulation in cellular signaling systems that control cell proliferation, differentiation and cell death. Protein kinase C (PKC), a family of serine/threonine kinases, plays an important role in the growth factor signal transduction pathway. PKCepsilon, however, is the only PKCepsilon isozyme that has been considered as an oncogene. It can contribute to malignancy by enhancing cell proliferation or by inhibiting cell death. This review focuses on how PKCepsilon collaborates with other signaling pathways, such as Ras/Raf/ERK and Akt, to regulate cell survival and cell death. We have also discussed how PKCepsilon mediates its antiapoptotic signal by altering the level or function of pro- and antiapoptotic Bcl-2 family members.

Fig. 1

Regulation of cell proliferation and cell death by PKCε. PKCε can cause disordered cell growth by stimulating the Raf/MEK/ERK pathway downstream of Ras proto-oncogene. It can also send survival signal via the PI3K/Akt pathway. PKCε can increase phosphorylation of Akt at Ser473 by facilitating interaction of Akt with a putative PDK2, such as DNA-PK. PKCε has been shown to increase the levels of antiapoptotic Bcl-2. It can interact with Bax and inhibit its activation, dimerization and translocation to mitochondria. It can also phosphorylate Bad and prevents its translocation to the mitochondria. An increase in the ratio of anti- to proapoptotic Bcl-2 family members in the mitochondria inhibits release of cytochrome c from the mitochondria and prevents activation of procaspase-9. PKCε can also inhibit receptor-initiated cell death pathway by decreasing the level of Bid and thus decreasing the amount of truncated Bid in the mitochondria. PKCε is a substrate for caspase-7. In response to apoptotic stimuli, full-length PKCε is cleaved at the hinge region to generate the C-terminal catalytic domain, which is active in the absence of cofactors.