AKT/PKB/Rac-protein kinases

Definition
Protein kinase B (PKB), also known as Akt (PKB/Akt), is a serine/threonine phosphoryl transferase and a downstream effector of the phosphoinositol–3 kinase (PI3K) signaling.

Discovery
The AKT protein kinase (also referred to as protein kinase B or Rac-protein kinase) was initially identified as an acute transforming component of the AKT8 virus isolated from a murine T cell lymphoma1, 2.

Classification
PKB/Akt belongs to the AGC subfamily of the protein kinase superfamily, which consists of 518 members in humans and is conserved from primitive metazoans to humans3.

Structural characteristics
The PKB subfamily comprises three mammalian isoforms, PKB , PKBß and PKB (Akt1, Akt2 and Akt3, respectively), which are products of distinct genes and share a conserved structure that includes three functional domains: an N-terminal pleckstrin homology (PH) domain, a central kinase domain, and a C-terminal regulatory domain containing the hydrophobic motif (HM) phosphorylation site [FxxF(S/T)Y]4.

Mechanism of action
As PKB is a downstream component of (PI3K) signaling, that is activated upon (1) autophosphorylation of receptor tyrosine kinases induced by ligands (such as insulin or other growth factors), (2) stimulation of G-protein-coupled receptors, or (3) activation of integrin signaling5, 6.

Functions
PKB/Akt plays an important role in all the cellular processes such as cell migration, survival, differentiation, as well as apoptosis7. Moreover, upregulation of Akt activity is recognized in variety of neoplasms, as well as chemoresistance8. To understand the role of PKB, tremendous efforts have been made to identify its physiological substrates. Most of the PKB substrates contain the minimal consensus sequence RxRxx(S/T), where x is any amino acid and S/T is the phosphorylation site. A genome–wide screen using this sequence motif will list more than 1,000 putative Akt phosphorylation targets in humans. Degenerate peptide library approach has also been used for screening various substrates for PKB/Akt9.

Reference:

1. Staal SP (1987). 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, 84(14):5034-5037.
2. Staal SP, Hartley JW (1988). Thymic lymphoma induction by the AKT8 murine retrovirus. J Exp Med, 167(3):1259-64.
3. Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC (2002). Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol Cell, 10(1):151-62.
4. Hanada M, Feng J, Hemmings BA (2004). Structure, regulation and function of PKB/AKT--a major therapeutic target. Biochim Biophys Acta, 1697(1-2):3-16.
5. Foster, F. M., Traer, C. J., Abraham, S. M. and Fry, M. J. (2003). The phosphoinositide (PI) 3-kinase family. J. Cell Sci., 116, 3037-3040.
6. Wymann, M. P., Zvelebil, M. and Laffargue, M.(2003). Phosphoinositide 3-kinase signalling–which way to target? Trends Pharmacol. Sci., 24, 366-376.
7. Song G, Ouyang G, Bao S (2005). The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med, 9(1):59-71
8. Kim D, Dan HC, Park S, Yang L, Liu Q, Kaneko S, Ning J, He L, Yang H, Sun M, Nicosia SV, Cheng JQ (2005). AKT/PKB signaling mechanisms in cancer and chemoresistance. Front Biosci., 10:975-87.
9. Obata T, Yaffe MB, Leparc GG, Piro ET, Maegawa H, Kashiwagi A, Kikkawa R, Cantley LC (2000). Peptide and protein library screening defines optimal substrate motifs for AKT/PKB. J Biol Chem, 275(46):36108-36115.