AKT protein family, which members are also called
protein kinaseA protein kinase is a kinase enzyme that modifies other proteins by chemically adding phosphate groups to them . Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins...
s B (PKB) plays an important role in
mammalianMammals are a class of vertebrate animals whose females are characterized by the possession of mammary glands while both males and females are characterized by sweat glands, hair, three middle ear bones used in hearing, and a neocortex region in the brain.Mammals are divided into three main...
cellular signaling.
In humans, there are three genes in the "Akt family":
Akt1RAC-alpha serine/threonine-protein kinase is an enzyme that in humans is encoded by the AKT1 gene.Mice lacking Akt1 display a 25% reduction in body mass, indicating that Akt1 is critical for transmitting growth promoting signals, most likely via the igf1 receptor...
,
Akt2RAC-beta serine/threonine-protein kinase is an enzyme that in humans is encoded by the AKT2 gene.-Interactions:AKT2 has been shown to interact with TCL1A, APPL1, SH3RF1 and CHUK.-Further reading:...
, and
Akt3RAC-gamma serine/threonine-protein kinase is an enzyme that in humans is encoded by the AKT3 gene.-Interactions:AKT3 has been shown to interact with Protein kinase Mζ.-Further reading:...
. These genes code for
enzymeEnzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process are called substrates, and the enzyme converts them into different molecules, called the products. Almost all processes in a biological cell need enzymes to occur at...
s that are members of the
serine/threonine-specific protein kinaseSerine/threonine protein kinases phosphorylate the OH group of serine or threonine .At least 125 of the 500+ human protein kinases are serine/threonine kinases .-Regulation:...
family .
Akt1 is involved in cellular survival pathways, by inhibiting
apoptoticApoptosis is the process of programmed cell death that may occur in multicellular organisms. Programmed cell death involves a series of biochemical events leading to a characteristic cell morphology and death; in more specific terms, a series of biochemical events that lead to a variety of...
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.
AKT protein family, which members are also called
protein kinaseA protein kinase is a kinase enzyme that modifies other proteins by chemically adding phosphate groups to them . Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins...
s B (PKB) plays an important role in
mammalianMammals are a class of vertebrate animals whose females are characterized by the possession of mammary glands while both males and females are characterized by sweat glands, hair, three middle ear bones used in hearing, and a neocortex region in the brain.Mammals are divided into three main...
cellular signaling.
Family members
In humans, there are three genes in the "Akt family":
Akt1RAC-alpha serine/threonine-protein kinase is an enzyme that in humans is encoded by the AKT1 gene.Mice lacking Akt1 display a 25% reduction in body mass, indicating that Akt1 is critical for transmitting growth promoting signals, most likely via the igf1 receptor...
,
Akt2RAC-beta serine/threonine-protein kinase is an enzyme that in humans is encoded by the AKT2 gene.-Interactions:AKT2 has been shown to interact with TCL1A, APPL1, SH3RF1 and CHUK.-Further reading:...
, and
Akt3RAC-gamma serine/threonine-protein kinase is an enzyme that in humans is encoded by the AKT3 gene.-Interactions:AKT3 has been shown to interact with Protein kinase Mζ.-Further reading:...
. These genes code for
enzymeEnzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process are called substrates, and the enzyme converts them into different molecules, called the products. Almost all processes in a biological cell need enzymes to occur at...
s that are members of the
serine/threonine-specific protein kinaseSerine/threonine protein kinases phosphorylate the OH group of serine or threonine .At least 125 of the 500+ human protein kinases are serine/threonine kinases .-Regulation:...
family .
Akt1 is involved in cellular survival pathways, by inhibiting
apoptoticApoptosis is the process of programmed cell death that may occur in multicellular organisms. Programmed cell death involves a series of biochemical events leading to a characteristic cell morphology and death; in more specific terms, a series of biochemical events that lead to a variety of...
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
oncogeneAn oncogene is a gene that, when mutated or expressed at high levels, helps turn a normal cell into a tumor cell.Many cells normally undergo a programmed form of death . Activated oncogenes can cause those cells to survive and proliferate instead...
in the transforming
retrovirusA retrovirus is an RNA virus that is replicated in a host cell via the enzyme reverse transcriptase to produce DNA from its RNA genome. The DNA is then incorporated into the host's genome by an integrase enzyme. The virus thereafter replicates as part of the host cell's DNA...
, AKT8. AKT8 was isolated from an AKR mouse spontaneous thymoma cell line by cocultivation with an indicator mink cell line. The transforming cellular sequences, v-akt, were cloned from a transformed mink cell clone and these sequences were used to identify Akt1 and Akt2 in a human clone library. AKT8 was isolated by Stephen Staal in the laboratory of Wallace P. Rowe; he subsequently cloned v-akt and human AKT1 and AKT2 while on staff at the Johns Hopkins Oncology Center.
Akt2 is an important signaling molecule in the Insulin signaling pathway. It is required to induce glucose transport.
These separate roles for Akt1 and Akt2 were demonstrated by studying mice in which either the Akt1 or the Akt2 gene was deleted, or "knocked out". 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 resistanceInsulin resistance is the condition in which normal amounts of insulin are inadequate to produce a normal insulin response from fat, muscle and liver cells. Insulin resistance in fat cells reduces the effects of insulin and results in elevated hydrolysis of stored triglycerides in the absence of...
), again consistent with the idea that Akt2 is more specific for the
insulin receptorIn molecular biology, the insulin receptor is a transmembrane receptor that is activated by insulin. It belongs to the large class of tyrosine kinase receptors....
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.
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', 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.
Binding phospholipids
Akt possesses a
protein domainA protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
known as a PH domain, or
Pleckstrin Homology domainPleckstrin homology domain 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....
, named after
PleckstrinPleckstrin is a protein found in platelets. The name derives from platelet and leukocyte C kinase substrate and the KSTR string of amino acids.It is the source of the name pleckstrin homology domain....
, the protein in which it was first discovered. This domain binds to
phosphoinositidesPhosphatidylinositol is a negatively charged phospholipid and a minor component in the cytosolic side of eukaryotic cell membranes....
with high affinity. In the case of the PH domain of Akt, it binds either
phosphatidylinositol (3,4,5)-trisphosphatePhosphatidylinositol -trisphosphate commonly abbreviated to PIP3 is the product of the class I phosphoinositide 3-kinases phosphorylation on phosphatidylinositol -bisphosphate .-Function:PIP3 is a part of the phosphatidylinositol bisphosphate Lipid signaling...
(PtdIns(3,4,5)
P3 aka PIP
3) or
phosphatidylinositol (3,4)-bisphosphatePhosphatidylinositol -bisphosphate is a minor phospholipid component of cell membranes, yet an important second messenger...
(PtdIns(3,4)
P2 aka PI(3,4)P
2). This is useful for control of cellular signaling because the di-phosphorylated phosphoinositide PtdIns(4,5)P
2 is only phosphorylated by the family of enzymes, PI 3-kinases (
phosphoinositide 3-kinasePhosphoinositide 3-kinases are a family of related intracellular Signal transducer enzymes capable of phosphorylating the 3 position hydroxyl group of the inositol ring of phosphatidylinositol . They are also known as phosphatidylinositol-3-kinases...
or PI3K), 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 kinaseA tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a tyrosine residue in a protein. Tyrosine kinases are a subgroup of the larger class of protein kinases...
such as the
insulin receptorIn molecular biology, the insulin receptor is a transmembrane receptor that is activated by insulin. It belongs to the large class of tyrosine kinase receptors....
. Once activated, PI 3-kinases phosphorylates PtdIns(4,5)P
2 to form PtdIns(3,4,5)P
3.
Phosphorylation
Once correctly positioned in 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 (
MAPKAPK2MAP kinase-activated protein kinase 2 is an enzyme that in humans is encoded by the MAPKAPK2 gene.-Interactions:MAPKAPK2 has been shown to interact with MAPK14, AKT1, PHC2 and SHC1.-Further reading:...
) can also serve as PDK2. Phosphorylation by mTORC2 stimulates the subsequent phosphorylation of Akt by PDK1. Activated Akt can then go on to activate or deactivate its myriad substrates via its kinase activity.
Besides being a downstream effector of PI 3-kinases, Akt may also be activated in a PI 3-kinase-independent manner. Studies have suggested that
cAMPCAMP may stand for:* Cyclic adenosine monophosphate * Cathelicidin antimicrobial peptide* Campaign Against Marijuana Planting* Central Atlantic Magmatic Province* CAMP, an Italian manufacturer of climbing equipment....
-elevating agents could activate Akt through protein kinase A (
PKAPKA or pKa may be:* Protein kinase A, a cAMP activated protein kinase* pKa, the symbol for Acid dissociation constant* Pi Kappa Alpha, the North-American social fraternity* Public Key Authentication...
), 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 suppressorA tumor suppressor gene, or antioncogene, is a gene that protects a cell from one step on the path to cancer. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes.-Two-hit hypothesis:Unlike...
PTENIn molecular biology, phosphatase and tensin homolog is a protein which in humans is encoded by the PTEN gene. Mutations of this gene are a step in the development of many cancers....
, which works essentially as the opposite of PI3K mentioned above. PTEN acts as a
phosphataseA phosphatase is an enzyme that removes a phosphate group from its substrate by hydrolysing phosphoric acid monoesters into a phosphate ion and a molecule with a free hydroxyl group . This action is directly opposite to that of phosphorylases and kinases, which attach phosphate groups to their...
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 the all 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,
SHIP1Phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 1 is an enzyme that in humans is encoded by the INPP5D gene.-Interactions:INPP5D has been shown to interact with DOK2, LYN, CD22, Grb2, CRKL, CD31, DOK1 and SHC1.-Further reading:...
and
SHIP2Phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 2 is an enzyme that in humans is encoded by the INPPL1 gene.-Interactions:INPPL1 has been shown to interact with BCAR1, SORBS1, FLNC and SHC1.-Further reading:...
. These poly-phosphate inositil phosphatases dephosphorylate PtdIns(3,4,5)P3 to form PtdIns(3,4)P2.
Protein phosphatases
The phosphatases in the
PHLPPThe PHLPP isoforms are a pair of protein phosphatases, PHLPP1 and PHLPP2, which are important regulators of Akt serine-threonine kinases and conventional/novel protein kinase C isoforms...
family,
PHLPP1The PHLPP isoforms are a pair of protein phosphatases, PHLPP1 and PHLPP2, which are important regulators of Akt serine-threonine kinases and conventional/novel protein kinase C isoforms...
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
metabolismMetabolism is the set of chemical reactions that occur in living organisms to maintain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories. Catabolism breaks down organic matter,...
by binding and regulating many downstream effectors, e.g.
Nuclear Factor-κBNF-κB is a protein complex that controls the transcription of DNA. NF-κB is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens...
, Bcl-2 family proteins and murine double minute 2 (
MDM2Mdm2 is an important negative regulator of the p53 tumor suppressor. It is the name of a gene as well as the protein encoded by that gene. Mdm2 protein functions both as an E3 ubiquitin ligase that recognizes the N-terminal trans-activation domain of the p53 tumor suppressor and an inhibitor of...
).
Cell survival
Akt could promote growth factor-mediated cell survival both directly and indirectly.
BADThe Bcl-2-associated death promoter protein is a pro-apoptotic member of the Bcl-2 gene family which is involved in initiating apoptosis. It does not contain a C-terminal transmembrane domain for outer mitochondrial membrane and nuclear envelope targeting, unlike most other members of the Bcl-2...
is a pro-apoptotic protein of the
Bcl-2Bcl-2 is the prototype for a family of mammalian genes and the proteins they produce. They govern mitochondrial outer membrane permeabilization and can be either pro-apoptotic or anti-apoptotic . There are a total of 25 genes in the Bcl-2 family known to date...
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-κBNF-κB is a protein complex that controls the transcription of DNA. NF-κB is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens...
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 cycleThe cell cycle, or cell-division cycle, is the series of events that take place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
. 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 (
GLUT4GLUT4 is the insulin-regulated glucose transporter found in adipose tissues and striated muscle that is responsible for insulin-regulated glucose disposal.-Reaction to insulin:...
) to the plasma membrane. Glycogen synthase kinase 3 (
GSK-3Glycogen synthase kinase 3 is a serine/threonine protein kinase, that mediates the addition of phosphate molecules on certain serine and threonine amino acids in particular cellular substrates...
) 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
HCVHepatitis C virus is a small , enveloped, positive sense single strand RNA virus in the family Flaviviridae. Although Hepatitis A virus, Hepatitis B virus, and Hepatitis C virus have similar names , these are distinctly different viruses both genetically and clinically.-Structure:The hepatitis C...
induced
steatosisIn cellular pathology, steatosis is the process describing the abnormal retention of lipids within a cell. It reflects an impairment of the normal processes of synthesis and elimination of triglyceride fat. Excess lipid accumulates in vesicles that displace the cytoplasm...
.
Angiogenesis
Akt1 has also been implicated in
angiogenesisAngiogenesis is a physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over this, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for new blood vessel formation by...
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.
Further Reading
Los M, Maddika S, Erb B, Schulze-Osthoff K. Switching Akt: from survival signaling to deadly response. Bioessays. 2009 May;31(5):492-5. Review. PMID: 19319914
External links