AKT Serine-Threonine Kinases

The AKT serine-threonine kinases are the human homologue to the viral oncogene v-akt. They are also known as protein kinase B (PKB) due to their similarity to protein kinase A (PKA) and protein kinase C (PKC) (Manning BD et al.2007).

Three Akt genes (AKT-1, AKT -2 and AKT -3) have been identified in mammals, and the expression of the different proteins varies in tissues. The serine-threonine kinases Akt-1 and Akt-2 can be detected in almost all tissues. In contrast, the expression of the serine-threonine kinase Akt-3 is limited to some tissue types. In particular, this kinase is highly expressed in the brain, lung, heart and kidney (Koseoglu S et al. 2007).

Akt is an important effector protein in this signaling cascade and is phosphorylated at the cell membrane by phosphoinositide-dependent kinase-1 (PDK1) at the amino acid threonine 308 (Akt-1), 309 (Akt-2), and 305 (Akt-3), respectively, depending on the isoform. For complete activation, phosphorylation at the amino acid serine 473 (Akt-1), 474 (Akt-2) or 472 (Akt-3) is additionally required. This is carried out by phosphoinositide-dependent kinase-2 (PDK2. This is a group of different kinases that can phosphorylate Akt.

They include

• the integrin linked kinase (ILK)
• the Mammalian target-of-rapamycin complex 2(mTORC2)
• the protein kinase Cβ2
• the DNA-dependent protein kinase (DNA-PK)
• and the kinase "Ataxia telangiectasia mutated" (ATM).

AKT is an important effector protein in the PI3K/AKT pathway and is phosphorylated at the cell membrane depending on the isoform by PDK1 at the amino acid threonine 308 (Akt-1), 309 (Akt-2) or 305 (Akt-3). Phosphorylation at the serine position can also occur via autophosphorylation of AKT. Upon activation, AKT kinase regulatesthe activity of various proteins by transferring phosphate groups, which have an effect on cell growth and proliferation, influence cell metabolism, and promote cell survival . More than 100 substrates of Akt have now been identified, characterized by the sequence motif RXRXXS/T-B (R= arginine, X = any amino acid, S= serine, T = threonine and B = amino acid with hydrophobic residues) (Alessi DR et al. 1996). Their functions are only partially known so far. The substrates are phosphorylated at serine or threonine residues and are thereby activated or inhibited (Scheid MPet al. 2001).

1. Alessi DR et al.(1996) Molecular basis for the substrate specificity of protein kinase B; comparison with MAPKAP kinase-1 and p70 S6 kinase. FEBS Lett 399:333-338.
2. Chalhoub N et al (2009) PTEN and the PI3-kinase pathway in cancer. Annu Rev Pathol 4:127-150.
3. Engelman JA et al (2006) The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet7:606-619.
4. Kok K et al (2009) Regulation of phosphoinositide 3-kinase expression in health and disease. Trends Biochem Sci 34:115-27.
5. Koseoglu S et al.(2007) AKT1, AKT2 and AKT3-dependent cell survival is cell line-specific and knockdown of all three isoforms selectively induces apoptosis in 20 human tumor cell lines. Cancer Biol Ther 6:755-762.
6. Manning BD et al.(2007) AKT/PKB signaling: navigating downstream. Cell 129:1261- 1274.
7. Patrucco E et al. (2004) PI3Kgamma modulates the cardiac response to chronic pressure overload by distinct kinase-dependent and -independent effects. Cell 118:375-387.
8. Sasaki T et al. (2000) Function of PI3Kgamma in thymocyte development, T cell activation, and neutrophil migration. Science 287:1040-1046.
9. Scheid MPet al (2001) PKB/AKT: functional insights from genetic models. Nat Rev Mol Cell Biol 2:760-768.
10. Schuldt C (2012) Studies on the importance of the PI3K/Akt signaling pathway in acute lymphoblastic leukemia Dissertation for the degree doctor rerum naturalium (Dr. rer. nat.) of the Faculty of Mathematics and Natural Sciences of the University of Rostock.
11. Staal SP. Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: amplification of AKT1 in a primary human gastric adenocarcinoma. Proc Natl Acad Sci U S A. 1987 Jul;84(14):5034-7.