AKT

Akt, also known as Protein Kinase B (PKB), is a serine/threonine protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription and cell migration.

Family members
In humans, there are three genes in the "Akt family": Akt1, Akt2, and Akt3. These genes code for enzymes that are members of the non-specific serine/threonine-protein kinase family.

Akt1 is involved in cellular survival pathways, by inhibiting apoptotic processes. Akt1 is also able to induce protein synthesis pathways, and is therefore a key signaling protein in the cellular pathways that lead to skeletal muscle hypertrophy, and general tissue growth. Since it can block apoptosis, and thereby promote cell survival, Akt1 has been implicated as a major factor in many types of cancer. Akt (now also called Akt1) was originally identified as the oncogene in the transforming retrovirus, AKT8.

Akt2 is an important signaling molecule in the Insulin signaling pathway. It is required to induce glucose transport. In a mouse which is null for Akt1 but normal for Akt2, glucose homeostasis is unperturbed, but the animals are smaller, consistent with a role for Akt1 in growth. In contrast, mice which do not have Akt2, but have normal Akt1, have mild growth deficiency and display a diabetic phenotype (insulin resistance), again consistent with the idea that Akt2 is more specific for the insulin receptor signaling pathway.

The role of Akt3 is less clear, though it appears to be predominantly expressed in brain. It has been reported that mice lacking Akt3 have small brains.

Name
The name Akt does not refer to its function. Presumably, the "Ak" in Akt was a temporary classification name for a mouse strain developing spontaneous thymic lymphomas. The "t" stands for 'transforming' (no; 'thymoma' - see Discussion), the letter was added when a transforming retrovirus was isolated from the Ak strain, which was termed "Akt-8". When the oncogene encoded in this virus was discovered, it was termed v-Akt. Thus, the later identified human analogues were named accordingly.

Regulation
Akt[1] is involved in the PI3K/AKT/mTOR pathway and other signaling pathways.

Binding phospholipids
Akt possesses a protein domain known as a PH domain, or Pleckstrin Homology domain, named after Pleckstrin, the protein in which it was first discovered. This domain binds to phosphoinositides with high affinity. In the case of the PH domain of Akt, it binds either PIP3 (phosphatidylinositol (3,4,5)-trisphosphate, PtdIns(3,4,5)P3) or PIP2 (phosphatidylinositol (3,4)-bisphosphate, PtdIns(3,4)P2). This is useful for control of cellular signaling because the di-phosphorylated phosphoinositide PIP2 is only phosphorylated by the family of enzymes, PI 3-kinases (phosphoinositide 3-kinase or PI3-K), and only upon receipt of chemical messengers which tell the cell to begin the growth process. For example, PI 3-kinases may be activated by a G protein coupled receptor or receptor tyrosine kinase such as the insulin receptor. Once activated, PI 3-kinase phosphorylates PIP2 to form PIP3.

Phosphorylation
Once correctly positioned at the membrane via binding of PIP3, Akt can then be phosphorylated by its activating kinases, phosphoinositide dependent kinase 1 (PDPK1 at threonine 308) and mTORC2 (at serine 473). First, the mammalian target of rapamycin complex 2 (mTORC2); mTORC2 therefore functionally acts as the long-sought PDK2 molecule, although other molecules, including Integrin-linked kinase (ILK) and Mitogen-Activated Protein Kinase Activated Protein Kinase-2 (MAPKAPK2) can also serve as PDK2. Phosphorylation by mTORC2 stimulates the subsequent phosphorylation of Akt by PDPK1.

Activated Akt can then go on to activate or deactivate its myriad substrates (eg mTOR) via its kinase activity.

Besides being a downstream effector of PI 3-kinases, Akt may possibly also be activated in a PI 3-kinase-independent manner. Studies have suggested that cAMP-elevating agents could activate Akt through protein kinase A (PKA), although these studies are disputed and the mechanism of action is unclear.

Lipid phosphatases and PIP3
PI3K dependent Akt activation can be regulated through the tumor suppressor PTEN, which works essentially as the opposite of PI3K mentioned above. PTEN acts as a phosphatase to dephosphorylate PtdIns(3,4,5)P3 back to PtdIns(4,5)P2. This removes the membrane-localization factor from the Akt signaling pathway. Without this localization, the rate of Akt activation decreases significantly, as do all of the downstream pathways that depend on Akt for activation.

PIP3 can also be de-phosphorylated at the "5" position by the SHIP family of inositol phosphatases, SHIP1 and SHIP2. These poly-phosphate inositil phosphatases dephosphorylate PtdIns(3,4,5)P3 to form PtdIns(3,4)P2.

Protein phosphatases
The phosphatases in the PHLPP family, PHLPP1 and PHLPP2 have been shown to directly de-phosphorylate, and therefore inactivate, distinct Akt isoforms. PHLPP2 dephosphorylates Akt1 and Akt3, whereas PHLPP1 is specific for Akt 2 and Akt3.

Function
Akt regulates cellular survival and metabolism by binding and regulating many downstream effectors, e.g. Nuclear Factor-κB, Bcl-2 family proteins and murine double minute 2 (MDM2).

Cell survival
Akt could promote growth factor-mediated cell survival both directly and indirectly. BAD is a pro-apoptotic protein of the Bcl-2 family. Akt could phosphorylate BAD on Ser136, which makes BAD dissociate from the Bcl-2/Bcl-X complex and lose the pro-apoptotic function. Akt could also activate NF-κB via regulating IκB kinase (IKK), thus result in transcription of pro-survival genes.

Cell Cycle
Akt is known to play a role in the cell cycle. Under various circumstances, activation of Akt was shown to overcome cell cycle arrest in G1 and G2 phases. Moreover, activated Akt may enable proliferation and survival of cells that have sustained a potentially mutagenic impact and, therefore, may contribute to acquisition of mutations in other genes.

Metabolism
Akt2 is required for the insulin-induced translocation of glucose transporter 4 (GLUT4) to the plasma membrane. Glycogen synthase kinase 3 (GSK-3) could be inhibited upon phosphorylation by Akt, which results in promotion of glycogen synthesis. GSK3 is also involved in Wnt signaling cascade, so Akt might be also implicated in the Wnt pathway. Still unknown role in HCV induced steatosis.

Angiogenesis
Akt1 has also been implicated in angiogenesis and tumor development. Although deficiency of Akt1 in mice inhibited physiological angiogenesis, it enhanced pathological angiogenesis and tumor growth associated with matrix abnormalities in skin and blood vessels.

Clinical relevance
Akt is associated with tumor cell survival, proliferation, and invasiveness. The activation of Akt is also one of the most frequent alterations observed in human cancer and tumor cells. Tumor cells that have constantly active Akt may depend on Akt for survival. Therefore, understanding Akt and its pathways is important for the creation of better therapies to treat cancer and tumor cells. A mosaic activating mutation (c. 49G→A, p.Glu17Lys) in AKT1 is associated with the Proteus Syndrome, which causes overgrowth of skin, connective tissue, brain and other tissues Because of the Akt[1] functions above Akt inhibitors may treat cancers such as neuroblastoma. Some Akt inhibitors have undergone clinical trials. In 2007 VQD-002 had a phase I trial. In 2010 Perifosine has reached phase II.

Miltefosine is approved for leishmaniasis and under investigation for other indications including HIV.

AKT activation is associated with many malignancies, however, a research group from Massachusetts General Hospital and Harvard University unexpectedly observed a converse role for AKT and one of its downstream effector FOXOs in acute myeloid leukemia (AML). They claimed that low levels of AKT activity associated with elevated levels of FOXOs are required to maintain the function and immature state of leukemia-initiating cells (LICs). FOXOs are active, implying reduced Akt activity, in ∼40% of AML patient samples regardless of genetic subtype; and either activation of Akt or compound deletion of FoxO1/3/4 reduced leukemic cell growth in mouse model.