Protein kinase C isoforms: Multi-functional regulators of cell life and death

Abstract

The protein kinase C (PKC) family consists of 10 related serine/threonine protein kinases some of which are critical regulators of cell proliferation, survival and cell death. While early studies relied on broad spectrum chemical activators or inhibitors of this family, the generation of isoform specific tools has greatly facilitated our understanding of the contribution of specific PKC isoforms to cell proliferation and apoptosis. These studies suggest that PKC-alpha, PKC-epsilon, and the atypical PKC's, PKC-lambda/iota and PKC-zeta, preferentially function to promote cell proliferation and survival, while the novel isoform, PKC-delta is an important regulator of apoptosis. The essential role of this kinase family in both cell survival and apoptosis suggests that specific isoforms may function as molecular sensors, promoting cell survival or cell death depending on environmental cues. Given their central role in cell and tissue homeostasis, it is not surprising that the expression or activity of some of these kinases is altered in human diseases, particularly cancer.

Figure 1

The PKC superfamily. PKC isoforms contain four structurally conserved domains (C1-C4). The N-terminal regulatory domain contains a pseudosubstrate binding site (PS), and the DAG (C1) and Ca⁺⁺ C2, or “C2-like”) binding sites. The catalytic terminal domain contains the ATP binding domain (C3), the substrate binding site, and the kinase domain (C4). The regulatory and catalytic domains are separated by a flexible hinge region which is the site of cleavage of PKC-delta by caspase-3 in apoptotic cells.

Figure 2

Regulation of the proapoptotic function of PKC-delta. Under normal growth conditions PKC-delta is retained in the cytoplasm by a mechanism that is dependent upon the regulatory domain. Apoptotic signals result in tyrosine phosphorylation of the regulatory domain and allow nuclear accumulation of PKC-delta. Active capsase-3 likewise accumulates in the nucleus resulting in cleavage of PKC-delta and generation of delta-CF. Delta-CF localizes constitutively in the nucleus where it may regulate proteins involved in the cell damage response.