The survival kinases Akt and Pim as potential pharmacological targets

Abstract

The Akt and Pim kinases are cytoplasmic serine/threonine kinases that control programmed cell death by phosphorylating substrates that regulate both apoptosis and cellular metabolism. The PI3K-dependent activation of the Akt kinases and the JAK/STAT-dependent induction of the Pim kinases are examples of partially overlapping survival kinase pathways. Pharmacological manipulation of such kinases could have a major impact on the treatment of a wide variety of human diseases including cancer, inflammatory disorders, and ischemic diseases.

Figure 1

Domain structure of the Akt and Pim kinases. The structures of human Akt1, Akt2, and Akt3 consist of a pleckstrin homology domain (PH) that binds to PIP₃ at membrane surfaces, the kinase domain, and the regulatory domain. The 2 phosphorylation sites necessary for Akt activation are shown. The structures of human Pim-1, Pim-2, and Pim-3 demonstrate a conserved kinase domain and no regulatory domain. There are no required phosphorylation sites for Pim activation. Alternate start codons are depicted in Pim-2 leading to multiple Pim-2 isoforms that retain kinase activity.

Figure 2

Survival kinases regulate cell death through the phosphorylation of common substrates of the apoptotic machinery and cellular metabolism. PI3K generates PIP₃, and PTEN converts PIP₃ back to PIP₂, negatively regulating PI3K signaling. PIP3 recruits PDK1, ILK, and Akt to the cell membrane. PDK1, ILK, and the rictor-mTOR complex are important for the activation of Akt. Expression of both SGK1 and Pim kinases is inducible. Akt, SGK1, and Pim kinases share common substrates of the apoptosis machinery and cellular metabolism, depicted as color-coded overlapping boxes (see text for full description). PFK2, phosphofructokinase-2.