Akt/PKB Cell Signaling Pathway

The serine–threonine kinase Akt (also known as protein kinase B (PKB) plays a critical role in a broadly influential signaling network. Akt activation serves as a master switch for cellular signaling pathways by generating a multitude of intracellular responses through downstream targets and interacting partners. Akt has been implicated in diseases ranging from cancer and diabetes to neurodegeneration. Akt is one of the most actively studied kinases in both basic research and drug development. We offer a wide range of products to help with Akt research. 

Akt/PKB is expressed as three isoforms ^[1]

Common targets in the Akt/PKB Pathway:

An amino terminal pleckstrin homology (PH) domain, a central serine–threonine catalytic domain, and a small carboxy terminal regulatory domain characterize all the three isoforms. The PH domain binds to phosphatidylinositol-3,4-bisphosphate (PIP2) and phosphatidylinositol-3,4,5-trisphosphate (PIP3), products of PI3K. This binding causes Akt to locate to the plasma membrane, where it becomes phosphorylated by phosphoinositide-dependent kinase 1 (PDK1) on Thr308 in the activation loop of the catalytic domain. This phosphorylation leads to activation. Full activation requires phosphorylation at a second site (Ser473).

The mTOR–rictor complex (mTORC2) is the primary kinase for the second phosphorylation event, although other kinases like Ilk (integrin linked kinase) ^{[2, 3]}, PDK1 ^{[4, 5]}, DNA-dependent protein kinase (DNA-PK) ^{[6, 7]} and ATM (ataxia telangiectasia mutated) have also been identified ^[8].

Abnormal activation or blockage of the Akt/PKB pathway is implicated in tumor cell survival and proliferation. Thus, the Akt pathway is an attractive target for anticancer drug discovery ^[9]. Key targets for tumor suppression include PH domain Leucine-rich repeat Protein Phosphatase (PHLPP), phosphatase and tensin homolog (PTEN) and tuberous sclerosis complex (TSC) [10]. These targets provide suppression at multiple points throughout the pathway. PTEN dephosphorylates PIP3 and stops activation of Akt. PHLPP1/PHLPP2 negatively regulates PI3K and, in turn, regulates Akt ^[10]. TSC1 and TSC2 are activated by Akt and then hinder mTOR downstream ^[11].

1. Vivanco, I., et al. (2002) The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer 7: 489-501.
2. Persad, S., et al. (2000) Inhibition of integrin-linked kinase (ILK) suppresses activation of protein kinase B/Akt and induces cell cycle arrest and apoptosis of PTEN-mutant prostate cancer cells. Proc Natl Acad Sci USA 97: 3207-3212.
3. Balendram, A., et al. (1999) PDK1 acquires PDK2 activity in the presence of a synthetic peptide derived from the carboxyl terminus of PRK2. Curr Biol 9: 393-404.
4. Rong, J., Simons, M. (2012) Syndecan 4 regulation of PDK1-dependent Akt activation. Cellular Signaling 25: 101-105.
5. Feng, et al. (2004) Identification of a PKB/Akt hydrophobic motif Ser-473 kinase as DNA-dependent protein kinase. J Biol Chem 279: 41189-41196.
6. Yikun, L., et al. (2013) Protein phosphatase 2A and DNA-dependent protein kinase are involved in mediating rapamycin-induced Akt phosphorylation. J Biol Chem 288: 13215-13224.
7. Dong, L.Q., Liu, F. (2005) PDK2: the mission piece in the receptor tyrosine kinase signaling pathway puzzle. Am J Physiol Endocrinol Metab 289: E187-E196.
8. Cheng, J.Q., et al. (2005) The Akt/PKB pathway: molecular target for cancer drug discovery. Oncogene 24: 7482-7492.
9. Newton, A. & Trotman, L. (2014) Turning off AKT: PHLPP as a drug target. Annu Rev Pharmacol Toxicol 54: 537-558.
10. Hay, N. (2005) The Akt-mTOR tango and its relevance to cancer. Cancer Cell 8: 179-183.