Protein kinase B, Akt, also known as PKB or Rac, plays an important role in cell survival and apoptosis. Both growth and survival factors such as insulin can activate the Akt signaling pathway. Akt's Thr308 can be phosphorylated by PDK1. The PI3 Kinase-Akt signal pathway is a classic signal pathway. When PI3 kinase inhibitors such as LY294002 inhibit PI3 kinase, they usually inhibit Akt activation. PKB is highly homologous to PKA and PKC, so it is also called related to the A and C kinase (RAC-PK). This kinase has been proven to be a retroviral gene the encoded product of v-akt is also called Akt.

Figure 1. Ribbon Representation of crystal structure of Akt-1-inhibitor complexes.

Akt Activation

Akt is present in the cytosol in an inactive conformation until the cells are stimulated and transferred to the plasma membrane. The Akt PH domain has a high affinity for the second messenger PI(3,4,5)P3, preferentially over other phosphoinositide binding. Therefore, PI3K activity is required for translocation of Akt to the membrane. Interaction with PI(3,4,5)P3 causes conformational changes and exposure of the phosphorylation site Thr308 in the kinase domain and Ser473 in the C-terminal domain. Phosphorylation of T308 is partially activated by PDK1. Complete activation requires phosphorylation of S473, which can be catalyzed by a variety of proteins, including phosphoinositide-dependent kinase 2 (PDK2), integrin-linked kinase (ILK), a mechanism target for rapamycin complex (mTORC) and DNA-dependent protein kinase (DNA-PK). The regulation of Ser473 phosphorylation is not fully understood, but may also be affected by autophosphorylation after Thr308 phosphorylation. After stimulation, by dephosphorylation of serine/threonine phosphatase, PIP3 levels are reduced and Akt activity is attenuated.

Akt Pathway Proteins

The Akt pathway or the PI3K-Akt pathway is a signal transduction pathway that promotes the survival and growth of extracellular signals. The key proteins include PI3K (phosphatidylinositol 3-kinase) and Akt (protein kinase B). The initial stimulation of a growth factor causes activation of cell surface receptors and phosphorylation of PI3K. The activated PI3K then phosphorylates the lipid on the plasma membrane to form a second messenger phosphatidylinositol (3,4,5)-triphosphate (PIP3). Akt is a serine/threonine kinase that is recruited to the membrane by interacting with these phosphoinositide docking sites, so it can be fully activated. Activated Akt mediates downstream responses by phosphorylating a range of intracellular proteins, including cell survival, growth, proliferation, cell migration, and angiogenesis. This pathway is present in all cells of higher eukaryotes and is highly conserved. This pathway is highly regulated by a variety of mechanisms, often involving cross-talk with other signaling pathways. Problems mediated by the PI3K-Akt pathway can result in increased signaling activity. This is associated with a range of diseases such as cancer and type 2 diabetes. The primary antagonist of PI3K activity is PTEN (phosphatase and tensin homolog), a tumor suppressor that is frequently mutated or lost in cancer cells. Akt phosphorylates up to 100 different substrates, resulting in extensive effects on cells.

Clinical relevance

Akt is related to the survival, proliferation and invasiveness of tumor cells. Akt activation is also one of the most common changes in human cancer and tumor cells. Tumor cells with continuously active Akt may depend on the survival rate of Akt. Therefore, understanding Akt and its pathways is important for creating better treatments for cancer and tumor cells. Mosaic-activated mutations in AKT1 (c. 49G → A, p. Glu17Lys) are associated with Proteus syndrome and cause excessive growth of skin, connective tissue, brain and other tissues.

References

1. Sardiello M.; et al. A gene network regulating lysosomal biogenesis and function. Science.2009, 325 (5939): 473-477.
2. Basu S.; et al. " Akt phosphorylates the Yes-associated protein, YAP, to induce interaction with 14-3-3 and attenuation of p73-mediated apoptosis. Mol Cell. 2003,11 (1):11-23.