PKB, or c-Akt (the cellular homologue of the product of the AKT8 retrovirus, which has been linked to lymphomas in mice). At one time it was known as RAC-PK, because of its relatedness to the protein kinases A and C, but the name isn’t used anymore because of confusion with RAC the GTPase. pKB, the term for affinity constants, which dominated any Medline search for PKB up until a few years ago. in the mid 1990s, when it was shown that PKB is regulated by PI 3-kinase, a lipid kinase that everyone was trying to find effectors for. No. The really big excitement came when it transpired that PKB, through the actions of PI 3-kinase, transmits a survival signal that allows cells to suppress apoptosis. Strangely, only two studies have shown a direct genetic link between PKB and apoptosis. These looked at apoptosis in fly development during expression of PKB transgenes. PKB also has a role in glucose metabolism, protein synthesis and more. When cells receive a growth or survival stimulus, PKB is drawn to the plasma membrane where it is the target of upstream kinases (see Figure 1). One of these upstream kinases, PDK1 (3-phosphoinositide-dependent protein kinase 1), has been isolated and cloned, but there is probably another kinase that is also needed to phosphorylate PKB, such as the integrin-linked kinase (ILK). Besides the kinase domain, PKB contains a pleckstrin homology (PH) domain, which is the part that regulates association with lipids at the plasma membrane. Once activated, PKB phosphorylates a bunch of cytosolic proteins as well as nuclear proteins that regulate gene transcription. As you might expect, a lot of research has focused on targets that are directly involved in the apoptosis machinery. Proteins called ‘forkhead transcription factors’ are the most plausible because of a genetic link shown in worms. At varying levels of confidence we have the following candidates: human Caspase-9, Bad, IKKα, Raf, eNOS, BRCA1 and GSK3. All harbor the RXRXXS motif that, on the basis of peptide assays, PKB seems to prefer. PKB is expressed widely, and is conserved across all eukaryotic species examined, including worms and flies and probably even chickens. Small molecule inhibitors of PKB are likely to be sought, as these could provide a therapeutic advantage by shifting the apoptosis threshold in cancer cells. This might be a way of countering the effects of losing a tumor suppressor such as PTEN, which normally acts to inhibit PKB. Vanhaesebroeck B, Alessi, DR: The PI3K-PDK1 connection: more than just a road to PKB.Biochem J 2000, 346:561-576. Scheid MP, Woodgett JR: Protein kinases: six degrees of separation?Curr Biol 2000, 10:R191-R194. Coffer P, Jin J, Woodgett JR: Protein kinase B (c-Akt): a multifunctional mediator of phosphatidylinositol 3-kinase activation.Biochem J 1998, 335:1-13. Datta SR, Brunet A, Greenberg ME: Cellular survival: a play in three Akts.Genes Dev 1999, 13:2905-2927. Glazer RI: The protein kinase ABC's of signal transduction as targets for drug development.Curr Pharm Des 1998, 4:277-290.