- OMIM: 164730
- UniProt: P31749
- OMIM: 164731
- UniProt: P31751
- OMIM: 611 223
- UniProt: Q9Y243
The protein kinase B ( PKBα / β / γ ) ( genes: AKT1, AKT2, AKT3 ), three enzymes that transfer a phosphate group to other proteins ( protein kinases). These modified proteins are part of important signaling pathways in the body, and so are the PKB itself part of the signal transduction. The serine / threonine kinases, including PKB belong, have evolved with the eukaryotes. PKBα is formed in humans in all tissue types, as well PKBγ, but to a lesser extent. PKBβ is mainly expressed in insulin - sensitive tissues. Since PKBS are often overactive in tumor cells is at AKT1/2/3 to oncogenes.
- 5.1 AKT ( E17K )
Identification of AKT genes
The prototype AKT AKT1 gene was discovered in 1991 by three groups. The groups of Brian Hemmings and J. R. Woodgett investigated by homologous cloning cellular kinases that are similar to the protein kinases PKA and PKC and this kinase called PKBα or RAC -PK (protein kinase - related to PKA and PKC). The Working Group, however, characterized by a viral oncogene Tsichlis - v - AKT - as a transforming agent in the poorly characterized retrovirus AKT8 and thus found the viral counterpart of the eukaryotic serine / threonine kinase. Shortly afterwards, the highly homologous isoforms AKT2 and AKT3 were then cloned yet.
Isoforms and structure
All three AKT genes encode whose peptide sequence highly homologous protein kinase isoforms AKT1/PKBα, AKT2/PKBβ and AKT3/PKBγ with an N -terminal PH domain (PH = pleckstrin homology ), a central kinase domain and a C -terminal hydrophobic domain with a regulatory function. Of AKT3/PKBγ there are two splice variants of different C-terminal end.
Regulation of its kinase activity
For an adequate cell homeostasis, the activity of the kinase via various mechanisms must be checked:
- Secondary Messengers ( phospholipid derivatives) Phosphatidylinositol -3 ,4,5- trisphosphate ( PIP3 )
- Activating phosphorylation T308, S473 by other kinases
- Auto- phosphorylation
- Trans - phosphorylation
- Oligomerization with the oncogene TCL1
PKB signaling pathway
The protein kinase B has a central role in the regulation of various cellular processes such as growth, cell proliferation, cell cycle and metabolism.
In the signal above the PKB is activated by extracellular signals phosphoinositide 3-kinase (PI3K ), which is initiated by the generation of second messengers PIP3 from phosphatidylinositol -4 ,5- bisphosphate ( PIP2 ) the so-called PI3K/AKT-Signalweg.
The protein kinase B can with its PH domain binding to PIP3 and thereby recruited to the cell membrane. There, it is of the phosphoinositide -dependent kinase -1 ( PDK1 ) and another kinase in their amino acids serine (473) and threonine (308) and activated by phosphorylation. Activated PKB can then phosphorylate various substrates and thereby activate or inhibit. An enzyme, which acts against the mechanism is the phosphatase PTEN, which inactivates PIP3 by cleaving a phosphate group. PTEN is a typical tumor suppressor and is inactivated in many tumor clones by mutations. Such tumor cells with a loss- of-function in PTEN and the resulting over-active PKB are proliferative tumors with frequent resistance to chemotherapeutic agents.
In addition, there are a number of other proteins that interact directly with PKB and influence their activity. TCL1 is a known which can oligomerize in the cytosol of AKT through its PH domain, resulting in activation of the kinase activity and change in the subcellular localization of AKT. This was shown in biochemical assays that a TCL1 - dimer interacts with AKT- 2 molecules.
Substrates and physiological consequences
There are a number of alleged and described substrates of protein kinase B, and bring the very different physiological consequences. They all point to the consensus sequence RXRXXS / TB. Known target proteins of Akt are Bcl -2 proteins and proteases that play a role in apoptosis, forkhead transcription factors, as well as inhibitors of CDKs. The following table is adapted from Manning & Cantley (2007).
PKB / Akt and cancer
The fact that the AKT8 retrovirus in mice can induce a T- cellular lymphoma, underlined the importance of protein kinase B in the transformation and cancer development and led to many groups lined up their research in this direction. Due to its transformative property PKB / AKT can be referred to as an oncogene.
AKT ( E17K )
It was a mutation in the PH domain of AKT1 found that can cause cancer. This is a point mutation (G > A) at nucleotide 49, which leads to the change of amino acid 17 of the PH domain (glutamic acid is replaced with lysine ). This is called NUDE mutant AKT ( E17K ).
The mutation changes the conformation of the PH domain and AKT can bind to the membrane ( and are activated there), even if there is no PIP3 available. A regulation of AKT activation by phosphorylation of the PIP or the PI 3- kinase activity is no longer possible.
The above-mentioned mutant was found in 8 % of breast cancer, 6 % of colorectal cancers and 2% of ovarian cancer cases.
The kinase activity of the individual is as large as that of the wild type; However, more permanent kinases are active than in wild -type cells by the frequent membrane association. Thereby increasing anti-apoptotic signaling pathways and proliferation of favorable to be activated, which can eventually lead to the degeneration of the cells. In mice, the mutant caused, for example, with a probability of 60 % leukemia (wild-type: 0%).