Protein kinase B (PKB), also known as Akt, is the collective name of a set of three
serine/threonine-specific protein kinase
A serine/threonine protein kinase () is a kinase enzyme, in particular a protein kinase, that phosphorylation, phosphorylates the hydroxyl, OH group of the amino acid, amino-acid residues serine or threonine, which have similar side chains. ...
s that play key roles in multiple cellular processes such as
glucose metabolism
Glucose is a sugar with the molecular formula , which is often abbreviated as Glc. It is overall the most abundant monosaccharide, a subcategory of carbohydrates. It is mainly made by plants and most algae during photosynthesis from water and ...
,
apoptosis
Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
,
cell proliferation
Cell proliferation is the process by which ''a cell grows and divides to produce two daughter cells''. Cell proliferation leads to an exponential increase in cell number and is therefore a rapid mechanism of tissue growth. Cell proliferation ...
,
transcription, and
cell migration
Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryogenesis, embryonic development, wound healing and immune system, immune responses all require the orchestrated movemen ...
.
Family members - Isoforms
There are three different genes that encode
isoform
A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...
s of protein kinase B. These three genes are referred to as ''
AKT1
RAC(Rho family)-alpha serine/threonine-protein kinase is an enzyme that in humans is encoded by the ''AKT1'' gene. This enzyme belongs to the AKT subfamily of serine/threonine kinases that contain SH2 (Src homology 2-like) protein domains. It ...
'', ''
AKT2'', and ''
AKT3'' and encode the RAC alpha, beta, and gamma serine/threonine protein kinases respectively. The terms PKB and Akt may refer to the products of all three genes collectively, but sometimes are used to refer to PKB alpha and Akt1 alone.
Akt1
RAC(Rho family)-alpha serine/threonine-protein kinase is an enzyme that in humans is encoded by the ''AKT1'' gene. This enzyme belongs to the AKT subfamily of serine/threonine kinases that contain SH2 (Src homology 2-like) protein domains. It ...
is involved in cellular survival pathways, by inhibiting
apoptotic
Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemical events lead to characteristic cell changes ( morphology) and death. These ...
processes. Akt1 is also able to induce
protein synthesis
Protein biosynthesis, or protein synthesis, is a core biological process, occurring inside cells, balancing the loss of cellular proteins (via degradation or export) through the production of new proteins. Proteins perform a number of critica ...
pathways, and is therefore a key signaling protein in the cellular pathways that lead to skeletal muscle hypertrophy and general tissue growth. A mouse model with complete deletion of the Akt1 gene manifests growth retardation and increased spontaneous apoptosis in tissues such as testes and thymus.
Since it can block apoptosis and thereby promote cell survival, Akt1 has been implicated as a major factor in many types of cancer.
Akt1 is also a positive regulator of cell migration.
Akt1 was originally identified as the
oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels. in the transforming
retrovirus
A retrovirus is a type of virus that inserts a DNA copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell. After invading a host cell's cytoplasm, the virus uses its own reverse transcriptase e ...
, 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
Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...
phenotype (
insulin resistance
Insulin resistance (IR) is a pathological response in which cells in insulin-sensitive tissues in the body fail to respond normally to the hormone insulin or downregulate insulin receptors in response to hyperinsulinemia.
Insulin is a horm ...
), again consistent with the idea that Akt2 is more specific for the
insulin receptor
The insulin receptor (IR) is a transmembrane receptor that is activated by insulin, IGF-I, IGF-II and belongs to the large class of receptor tyrosine kinase. Metabolically, the insulin receptor plays a key role in the regulation of glucose h ...
signaling pathway.
Akt2 promotes cell migration as well.
The role of
Akt3 is less clear, though it appears to be predominantly expressed in the brain. It has been reported that mice lacking Akt3 have small brains.
Akt isoforms are overexpressed in a variety of human tumors, and, at the genomic level, are amplified in gastric adenocarcinomas (Akt1), ovarian (Akt2), pancreatic (Akt2) and breast (Akt2) cancers.
Name
The name Akt does not refer to its function. The "Ak" in Akt refers to the AKR mouse strain that develops spontaneous thymic lymphomas. The "t" stands for '
thymoma
A thymoma is a tumor originating from the epithelial cells of the thymus that is considered a rare neoplasm. Thymomas are frequently associated with neuromuscular disorders such as myasthenia gravis; thymoma is found in 20% of patients with myast ...
'; the letter was added when a transforming retrovirus was isolated from the Ak mouse strain, which was termed "Akt-8". The authors state, "Stock A Strain k AKR mouse originally inbred in the laboratory of Dr. C. P. Rhoads by K. B. Rhoads at the Rockefeller Institute." When the oncogene encoded in this virus was discovered, it was termed v-Akt. Thus, the more recently identified human analogs were named accordingly.
Regulation
Akt1 is involved in the
PI3K/AKT/mTOR pathway
The PI3K/AKT/mTOR pathway is an intracellular signaling pathway important in regulating the cell cycle. Therefore, it is directly related to cellular quiescence, proliferation, cancer, and longevity. PI3K activation phosphorylates and activates ...
and other signaling pathways.
Binding phospholipids
The Akt proteins possess a
protein domain
In molecular biology, a protein domain is a region of a protein's Peptide, polypeptide chain that is self-stabilizing and that Protein folding, folds independently from the rest. Each domain forms a compact folded Protein tertiary structure, thre ...
known as a PH domain, or
pleckstrin homology domain
Pleckstrin homology domain (PH domain) or (PHIP) is a protein domain of approximately 120 amino acids that occurs in a wide range of proteins involved in intracellular signaling or as constituents of the cytoskeleton.
This domain can bind phosph ...
, named after
pleckstrin, the protein in which it was first discovered. This domain binds to
phosphoinositides
Phosphatidylinositol or inositol phospholipid is a biomolecule. It was initially called "inosite" when it was discovered by Léon Maquenne and Johann Joseph von Scherer in the late 19th century. It was discovered in bacteria but later also found ...
with high affinity. In the case of the PH domain of the Akt proteins, it binds either PIP
3 (
phosphatidylinositol (3,4,5)-trisphosphate
Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)''P''3), abbreviated PIP3, is the product of the class I phosphoinositide 3-kinases' (PI 3-kinases) phosphorylation of phosphatidylinositol (4,5)-bisphosphate (PIP2). It is a phospholipid ...
, PtdIns(3,4,5)''P''
3) or PIP
2 (
phosphatidylinositol (3,4)-bisphosphate
Phosphatidylinositol (3,4)-bisphosphate (PtdIns(3,4)''P''2) is a minor phospholipid component of cell membranes, yet an important second messenger. The generation of PtdIns(3,4)''P''2 at the plasma membrane activates a number of important cell sig ...
, PtdIns(3,4)''P''
2). 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
Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...
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
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large protein family, group of evoluti ...
or
receptor tyrosine kinase
Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinas ...
such as the
insulin receptor
The insulin receptor (IR) is a transmembrane receptor that is activated by insulin, IGF-I, IGF-II and belongs to the large class of receptor tyrosine kinase. Metabolically, the insulin receptor plays a key role in the regulation of glucose h ...
. Once activated, PI 3-kinase phosphorylates PIP
2 to form PIP
3.
Phosphorylation
Once correctly positioned at the membrane via binding of
PIP3
Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)''P''3), abbreviated PIP3, is the product of the class I phosphoinositide 3-kinases' (PI 3-kinases) phosphorylation of phosphatidylinositol (4,5)-bisphosphate (PIP2). It is a phospholipid t ...
, Akt can then be phosphorylated by its activating kinases, phosphoinositide-dependent kinase-1 (
PDPK1
In the field of biochemistry, PDPK1 refers to the protein 3-phosphoinositide-dependent protein kinase-1, an enzyme which is encoded by the ''PDPK1'' gene in humans. It is implicated in the development and progression of melanomas.
Function
P ...
at threonine 308 in Akt1 and threonine 309 in Akt2) and the mammalian target of rapamycin complex 2 (
mTORC2
mTOR Complex 2 (mTORC2) is an acutely rapamycin-insensitive protein complex formed by serine/threonine kinase mTOR that regulates cell proliferation and survival, cell migration and cytoskeletal remodeling. The complex itself is rather large, ...
at serine 473 (Akt1) and 474 (Akt2)) which is found at high levels in the fed state,
first by mTORC2. mTORC2 therefore functionally acts as the long-sought PDK2 molecule, although other molecules, including
integrin-linked kinase
Integrin-linked kinase is an enzyme that in humans is encoded by the ILK gene involved with integrin-mediated signal transduction. Mutations in ''ILK'' are associated with cardiomyopathies. It is a 59kDa protein originally identified in a yeast- ...
(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 isoforms by PDPK1.
Activated Akt isoforms can then go on to activate or deactivate their myriad substrates (e.g.
mTOR
The mammalian target of rapamycin (mTOR), also referred to as the mechanistic target of rapamycin, and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the ''MTOR'' gene. ...
) via their kinase activity.
Besides being a downstream effector of PI 3-kinases, Akt isoforms can also be activated in a PI 3-kinase-independent manner.
ACK1 or
TNK2, a non-receptor tyrosine kinase, phosphorylates Akt at its tyrosine 176 residue, leading to its activation in PI 3-kinase-independent manner.
Studies have suggested that
cAMP
Camp may refer to:
Areas of confinement, imprisonment, or for execution
* Concentration camp, an internment camp for political prisoners or politically targeted demographics, such as members of national or minority ethnic groups
* Extermination ...
-elevating agents could also activate Akt through
protein kinase A
In cell biology, protein kinase A (PKA) is a family of serine-threonine kinases whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase (). PKA has several functions in the cell, in ...
(PKA) in the presence of insulin.
''O''-GlcNAcylation
Akt can be
''O''-GlcNAcylated by
OGT. ''O''-GlcNAcylation of Akt is associated with a decrease in T308 phosphorylation.
Ubiquitination
Akt1 is normally
phosphorylated
In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols:
:
This equation can be writt ...
at position T450 in the turn motif when Akt1 is translated. If Akt1 is not phosphorylated at this position, Akt1 does not fold in the right way. The T450-non-phosphorylated misfolded Akt1 is
ubiquitinated and degraded by the
proteasome
Proteasomes are essential protein complexes responsible for the degradation of proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases. Proteasomes are found inside all e ...
. Akt1 is also phosphorylated at T308 and S473 during
IGF-1
Insulin-like growth factor 1 (IGF-1), also called somatomedin C, is a hormone similar in molecular structure to insulin which plays an important role in childhood growth, and has anabolic effects in adults. In the 1950s IGF-1 was called " sulfa ...
response, and the resulting polyphosphorylated Akt is ubiquitinated partly by
E3 ligase
A ubiquitin ligase (also called an E3 ubiquitin ligase) is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin ...
NEDD4
E3 ubiquitin-protein ligase NEDD4, also known as neural precursor cell expressed developmentally down-regulated protein 4 (whence "NEDD4") is an enzyme that is, in humans, encoded by the ''NEDD4'' gene.
NEDD4 is an E3 ubiquitin ligase enzyme, tha ...
. Most of the ubiquitinated-phosphorylated-Akt1 is degraded by the proteasome, while a small amount of phosphorylated-Akt1 translocates to the nucleus in a ubiquitination-dependent way to phosphorylate its substrate. A cancer-derived mutant Akt1 (E17K) is more readily ubiquitinated and phosphorylated than the wild type Akt1. The ubiquitinated-phosphorylated-Akt1 (E17K) translocates more efficiently to the nucleus than the wild type Akt1. This mechanism may contribute to E17K-Akt1-induced cancer in humans.
Lipid phosphatases and PIP3
PI3K-dependent Akt1 activation can be regulated through the
tumor suppressor
A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell (biology), cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results ...
PTEN, which works essentially as the opposite of
PI3K
Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...
mentioned above.
PTEN acts as a
phosphatase
In biochemistry, a phosphatase is an enzyme that uses water to cleave a phosphoric acid Ester, monoester into a phosphate ion and an Alcohol (chemistry), alcohol. Because a phosphatase enzyme catalysis, catalyzes the hydrolysis of its Substrate ...
to dephosphorylate
PIP3
Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)''P''3), abbreviated PIP3, is the product of the class I phosphoinositide 3-kinases' (PI 3-kinases) phosphorylation of phosphatidylinositol (4,5)-bisphosphate (PIP2). It is a phospholipid t ...
back to
PIP2
Phosphatidylinositol 4,5-bisphosphate or PtdIns(4,5)''P''2, also known simply as PIP2 or PI(4,5)P2, is a minor phospholipid component of cell membranes. PtdIns(4,5)''P''2 is enriched at the plasma membrane where it is a substrate for a number of ...
. This removes the membrane-localization factor from the
Akt signaling pathway. Without this localization, the rate of
Akt1
RAC(Rho family)-alpha serine/threonine-protein kinase is an enzyme that in humans is encoded by the ''AKT1'' gene. This enzyme belongs to the AKT subfamily of serine/threonine kinases that contain SH2 (Src homology 2-like) protein domains. It ...
activation decreases significantly, as do all of the downstream pathways that depend on
Akt1
RAC(Rho family)-alpha serine/threonine-protein kinase is an enzyme that in humans is encoded by the ''AKT1'' gene. This enzyme belongs to the AKT subfamily of serine/threonine kinases that contain SH2 (Src homology 2-like) protein domains. It ...
for activation.
PIP3
Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)''P''3), abbreviated PIP3, is the product of the class I phosphoinositide 3-kinases' (PI 3-kinases) phosphorylation of phosphatidylinositol (4,5)-bisphosphate (PIP2). It is a phospholipid t ...
can also be de-phosphorylated at the "5" position by the SHIP family of inositol phosphatases,
SHIP1 and
SHIP2. These poly-phosphate inositol phosphatases dephosphorylate
PIP3
Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)''P''3), abbreviated PIP3, is the product of the class I phosphoinositide 3-kinases' (PI 3-kinases) phosphorylation of phosphatidylinositol (4,5)-bisphosphate (PIP2). It is a phospholipid t ...
to form
PIP2
Phosphatidylinositol 4,5-bisphosphate or PtdIns(4,5)''P''2, also known simply as PIP2 or PI(4,5)P2, is a minor phospholipid component of cell membranes. PtdIns(4,5)''P''2 is enriched at the plasma membrane where it is a substrate for a number of ...
.
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 Akt2 and Akt3.
Function
The Akt kinases regulate cellular survival
and
metabolism
Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...
by binding and regulating many downstream effectors, e.g.
Nuclear Factor-κB, Bcl-2 family proteins, master lysosomal regulator
TFEB and murine double minute 2 (
MDM2).
Cell survival
Akt kinases can promote growth factor-mediated cell survival both directly and indirectly.
BAD
Bad or BAD may refer to:
Common meanings
*Evil, the opposite of moral good
* Erroneous, inaccurate or incorrect
* Unhealthy, or counter to well-being
*Antagonist, the threat or obstacle of moral good
Acronyms
* BAD-2, a Soviet armored trolley ...
is a pro-apoptotic protein of the
Bcl-2
Bcl-2, encoded in humans by the ''BCL2'' gene, is the founding member of the Bcl-2 family of regulator proteins. BCL2 blocks programmed cell death (apoptosis) while other BCL2 family members can either inhibit or induce it. It was the first a ...
family. Akt1 can phosphorylate BAD on Ser136,
which makes BAD dissociate from the Bcl-2/Bcl-X complex and lose the pro-apoptotic function.
Akt1 can also activate
NF-κB
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a family of transcription factor protein complexes that controls transcription (genetics), transcription of DNA, cytokine production and cell survival. NF-κB is found i ...
via regulating
IκB kinase
The IκB kinase (IkappaB kinase or IKK) is an enzyme complex that is involved in propagating the cellular response to inflammation, specifically the regulation of lymphocytes.
The IκB kinase enzyme complex is part of the upstream NF-κB signal ...
(IKK), thus result in transcription of pro-survival genes.
Cell cycle
The Akt isoforms are known to play a role in the
cell cycle
The cell cycle, or cell-division cycle, is the sequential series of events that take place in a cell (biology), cell that causes it to divide into two daughter cells. These events include the growth of the cell, duplication of its DNA (DNA re ...
. Under various circumstances, activation of Akt1 was shown to overcome cell cycle arrest in G1
and G2
phases. Moreover, activated Akt1 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
Glucose transporter type 4 (GLUT4), also known as solute carrier family 2, facilitated glucose transporter member 4, is a protein encoded, in humans, by the ''SLC2A4'' gene. GLUT4 is the insulin-regulated glucose transporter found primarily in ad ...
) to the
plasma membrane
The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...
. Glycogen synthase kinase 3 (
GSK-3) could be inhibited upon phosphorylation by Akt, which results in increase of glycogen synthesis. GSK3 is also involved in
Wnt signaling cascade, so Akt might be also implicated in the Wnt pathway.
Its role in
HCV induced
steatosis
Steatosis, also called fatty change, is abnormal retention of fat (lipids) within a cell or organ. Steatosis most often affects the liver – the primary organ of lipid metabolism – where the condition is commonly referred to as fatty liver dis ...
is unknown.
Lysosomal biogenesis and autophagy
Akt1 regulates
TFEB, a master controller of lysosomal biogenesis,
by direct phosphorylation at serine 467.
Phosphorylated TFEB is excluded from the nucleus and less active.
Pharmacological inhibition of Akt promotes nuclear translocation of
TFEB, lysosomal biogenesis and autophagy.
Angiogenesis
Akt1 has also been implicated in
angiogenesis
Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature mainly by processes of sprouting and ...
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 proteins are 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 the Akt proteins and their 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
Proteus syndrome is a rare genetic disorder that can cause tissue overgrowth involving all three Germ layer, embryonic lineages. Patients with Proteus syndrome tend to have an increased risk of embryonic tumor development.Freedberg, et al. (2003). ...
, which causes overgrowth of skin, connective tissue, brain and other tissues.
Akt inhibitors
Akt inhibitors may treat cancers such as
neuroblastoma
Neuroblastoma (NB) is a type of cancer that forms in certain types of nerve tissue. It most frequently starts from one of the adrenal glands but can also develop in the head, neck, chest, abdomen, or Vertebral column, spine. Symptoms may include ...
. Some Akt inhibitors have undergone clinical trials. In 2007
VQD-002 had a phase I trial.
In 2010
Perifosine reached phase II.
but it failed phase III in 2012.
Miltefosine
Miltefosine, sold under the trade name Impavido among others, is a medication mainly used to treat leishmaniasis and free-living amoeba infections such as '' Naegleria fowleri'' and '' Balamuthia mandrillaris''. This includes the three forms of ...
is approved for
leishmaniasis
Leishmaniasis is a wide array of clinical manifestations caused by protozoal parasites of the Trypanosomatida genus ''Leishmania''. It is generally spread through the bite of Phlebotominae, phlebotomine Sandfly, sandflies, ''Phlebotomus'' an ...
and under investigation for other indications including HIV.
Akt1 is now thought to be the "key" for cell entry by
HSV-1 and
HSV-2 (herpes virus: oral and genital, respectively). Intracellular
calcium
Calcium is a chemical element; it has symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to it ...
release by the cell allows for entry by the herpes virus; the virus activates Akt1, which in turn causes the release of calcium. Treating the cells with Akt inhibitors before virus exposure leads to a significantly lower rate of infection.
[
*]
MK-2206 reported phase 1 results for advanced solid tumors in 2011,
and subsequently has undergone numerous phase II studies for a wide variety of cancer types.
In 2013
AZD5363 reported phase I results regarding solid tumors. with a study of AZD5363 with
olaparib reporting in 2016.
Ipatasertib is in phase II trials for breast cancer.
Decreased Akt isoforms can cause deleterious effects
Akt isoform activation is associated with many malignancies; however, a research group from
Massachusetts General Hospital
Massachusetts General Hospital (Mass General or MGH) is a teaching hospital located in the West End neighborhood of Boston, Massachusetts. It is the original and largest clinical education and research facility of Harvard Medical School/Harvar ...
and
Harvard University
Harvard University is a Private university, private Ivy League research university in Cambridge, Massachusetts, United States. Founded in 1636 and named for its first benefactor, the History of the Puritans in North America, Puritan clergyma ...
unexpectedly observed a converse role for Akt and one of its downstream effector
FOXOs in
acute myeloid leukemia
Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with haematopoiesis, normal blood cell production. Sympt ...
(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 a mouse model.
Hyperactivation of Akt1 can cause deleterious effects
Two studies show that Akt1 is involved in Juvenile Granulosa Cell tumors (JGCT). In-frame duplications in the pleckstrin-homology domain (PHD) of the protein were found in more than 60% of JGCTs occurring in girls under 15 years of age. The JGCTs without duplications carried point mutations affecting highly conserved residues. The mutated proteins carrying the duplications displayed a non-wild-type subcellular distribution, with a marked enrichment at the plasma membrane. This led to a striking degree of Akt1 activation demonstrated by a strong phosphorylation level and corroborated by reporter assays.
Analysis by RNA-Seq pinpointed a series of differentially expressed genes, involved in cytokine and hormone signaling and cell division-related processes. Further analyses pointed to a possible dedifferentiation process and suggested that most of the transcriptomic dysregulations might be mediated by a limited set of transcription factors perturbed by Akt1 activation. These results incriminate somatic mutations of Akt1 as major probably driver events in the pathogenesis of JGCTs.
See also
*
Akt/PKB signaling pathway
The Akt signaling pathway or PI3K-Akt signaling pathway is a signal transduction pathway that promotes survival and growth in response to extracellular signals. Key proteins involved are PI3K (phosphatidylinositol 3-kinase) and Akt (protein kinase ...
*
Discovery and development of mTOR inhibitors
mTOR inhibitors are a drug class, class of drugs used to treat several human diseases, including cancer, autoimmune diseases, and neurodegeneration. They function by inhibiting the mammalian target of rapamycin (mTOR) (also known as the mechanist ...
*
PI3K/AKT/mTOR pathway
The PI3K/AKT/mTOR pathway is an intracellular signaling pathway important in regulating the cell cycle. Therefore, it is directly related to cellular quiescence, proliferation, cancer, and longevity. PI3K activation phosphorylates and activates ...
*
Akt inhibitor
*
PTEN
References
Further reading
*
*
External links
*
{{DEFAULTSORT:Akt
EC 2.7.11
Protein kinases