Protein kinase B (PKB), also referred to as Akt, is a serine/threonine-specific protein kinase that performs a key position in a number of mobile processes reminiscent of glucose metabolism, apoptosis, cell proliferation, transcription, and cell migration.
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Members of the family – Isoforms[edit]
Akt1 is concerned in mobile survival pathways, by inhibiting apoptotic processes. Akt1 can also be capable of induce protein synthesis pathways, and is subsequently a key signaling protein within the mobile pathways that result in skeletal muscle hypertrophy, and basic tissue progress. Mouse mannequin with full deletion of Akt1 manifests progress retardation and elevated spontaneous apoptosis in tissues reminiscent of testes and thymus.[3] Since it might block apoptosis, and thereby promote cell survival, Akt1 has been implicated as a significant factor in lots of kinds of most cancers. Akt (now additionally known as Akt1) was initially recognized because the oncogene within the reworking retrovirus, AKT8.[4]
Akt2 is a vital signaling molecule within the insulin signaling pathway. It’s required to induce glucose transport. In a mouse which is null for Akt1 however regular for Akt2, glucose homeostasis is unperturbed, however the animals are smaller, per a task for Akt1 in progress. In distinction, mice which should not have Akt2, however have regular Akt1, have delicate progress deficiency and show a diabetic phenotype (insulin resistance), once more per the concept that Akt2 is extra particular for the insulin receptor signaling pathway.[5]
Akt isoforms are overexpressed in quite a lot of human tumors, and, on the genomic stage, are amplified in gastric adenocarcinomas (Akt1), ovarian (Akt2), pancreatic (Akt2) and breast (Akt2) most cancers.[6][7]
The position of Akt3 is much less clear, although it seems to be predominantly expressed within the mind. It has been reported that mice missing Akt3 have small brains.[8]
Title[edit]
The title Akt doesn’t check with its perform. The “Ak” in Akt refers back to the AKR mouse pressure that develops spontaneous thymic lymphomas. The “t” stands for ‘thymoma’; the letter was added when a reworking retrovirus was remoted from the Ak pressure, which was termed “Akt-8”. When the oncogene encoded on this virus was found, it was termed v-Akt. Thus, the later recognized human analogues have been named accordingly.[citation needed]
Regulation[edit]
Akt1 is concerned within the PI3K/AKT/mTOR pathway and different signaling pathways. [9][citation needed]
Binding phospholipids[edit]
Akt possesses a protein area generally known as a PH area, or pleckstrin homology area, named after pleckstrin, the protein by which it was first found. This area binds to phosphoinositides with excessive affinity. Within the case of the PH area of Akt, it binds both PIP3 (phosphatidylinositol (3,4,5)-trisphosphate, PtdIns(3,4,5)P3) or PIP2 (phosphatidylinositol (3,4)-bisphosphate, PtdIns(3,4)P2).[10] That is helpful for management of mobile signaling as a result of the di-phosphorylated phosphoinositide PIP2 is barely phosphorylated by the household of enzymes, PI 3-kinases (phosphoinositide 3-kinase or PI3-Ok), and solely upon receipt of chemical messengers which inform the cell to start the expansion course of. For instance, PI 3-kinases could also be activated by a G protein coupled receptor or receptor tyrosine kinase such because the insulin receptor. As soon as activated, PI 3-kinase phosphorylates PIP2 to kind PIP3.
Phosphorylation[edit]
As soon as appropriately positioned on the membrane by way of binding of PIP3, Akt can then be phosphorylated by its activating kinases, phosphoinositide dependent kinase 1 (PDPK1 at threonine 308) and the mammalian goal of rapamycin complicated 2 (mTORC2 at serine 473) which is discovered at excessive ranges within the fed state, [11][12] first by mTORC2. mTORC2 subsequently functionally acts because the long-sought PDK2 molecule, though different molecules, together with integrin-linked kinase (ILK) and mitogen-activated protein kinase-activated protein kinase-2 (MAPKAPK2) may also function PDK2. Phosphorylation by mTORC2 stimulates the next phosphorylation of Akt by PDPK1.
Activated Akt can then go on to activate or deactivate its myriad substrates (e.g. mTOR) by way of its kinase exercise.
In addition to being a downstream effector of PI 3-kinases, Akt will also be activated in a PI 3-kinase-independent method.[13] ACK1 or TNK2, a non-receptor tyrosine kinase, phosphorylates Akt at its tyrosine 176 residue, resulting in its activation in PI 3-kinase-independent method.[13] Research have instructed that cAMP-elevating brokers may additionally activate Akt by way of protein kinase A (PKA) within the presence of insulin.[14]
O-GlcNAcylation[edit]
Akt may be O-GlcNAcylated by OGT. O-GlcNAcylation of Akt is related to a lower in T308 phosphorylation.[15]
Ubiquitination[edit]
Akt is generally phosphorylated at place T450 within the flip motif when Akt is translated. If Akt will not be phosphorylated at this place, Akt doesn’t fold in the proper approach. The T450-non-phosphorylated misfolded Akt is ubiquitinated and degraded by the proteasome. Akt can also be phosphorylated at T308 and S473 throughout IGF-1 response, and the ensuing polyphosphorylated Akt is ubiquitinated partly by E3 ligase NEDD4. A lot of the ubiquitinated-phosphorylated-Akt is degraded by the proteasome, whereas a small quantity of phosphorylated-Akt translocates to the nucleus in a ubiquitination-dependent approach to phosphorylate its substrate. A cancer-derived mutant Akt (E17K) is extra readily ubiquitinated and phosphorylated than the wild kind Akt. The ubiquitinated-phosphorylated-Akt (E17K) translocates extra effectively to the nucleus than the wild kind Akt. This mechanism could contribute to E17K-Akt-induced most cancers in people.[16]
Lipid phosphatases and PIP3[edit]
PI3K-dependent Akt activation may be regulated by way of the tumor suppressor PTEN, which works primarily as the other of PI3K talked about above.[17] PTEN acts as a phosphatase to dephosphorylate PIP3 again to PIP2. This removes the membrane-localization issue from the Akt signaling pathway. With out this localization, the speed of Akt activation decreases considerably, as do the entire downstream pathways that rely upon Akt for activation.
PIP3 will also be de-phosphorylated on the “5” place by the SHIP household of inositol phosphatases, SHIP1 and SHIP2. These poly-phosphate inositol phosphatases dephosphorylate PIP3 to kind PIP2.
Protein phosphatases[edit]
The phosphatases within the PHLPP household, PHLPP1 and PHLPP2 have been proven to straight de-phosphorylate, and subsequently inactivate, distinct Akt isoforms. PHLPP2 dephosphorylates Akt1 and Akt3, whereas PHLPP1 is restricted for Akt 2 and Akt3.[citation needed]
Operate[edit] – “protein kinase b”
Akt regulates mobile survival[18] and metabolism by binding and regulating many downstream effectors, e.g. Nuclear Issue-κB, Bcl-2 household proteins, grasp lysosomal regulator TFEB and murine double minute 2 (MDM2).
Cell survival[edit]
Akt may promote progress factor-mediated cell survival each straight and not directly. BAD is a pro-apoptotic protein of the Bcl-2 household. Akt may phosphorylate BAD on Ser136,[19] which makes BAD dissociate from the Bcl-2/Bcl-X complicated and lose the pro-apoptotic perform.[20] Akt may additionally activate NF-κB by way of regulating IκB kinase (IKK), thus lead to transcription of pro-survival genes.[21]
Cell cycle[edit]
Akt is understood to play a task within the cell cycle. Below numerous circumstances, activation of Akt was proven to beat cell cycle arrest in G1[22] and G2[23] phases. Furthermore, activated Akt could allow proliferation and survival of cells which have sustained a probably mutagenic affect and, subsequently, could contribute to acquisition of mutations in different genes.
Metabolism[edit]
Akt2 is required for the insulin-induced translocation of glucose transporter 4 (GLUT4) to the plasma membrane. Glycogen synthase kinase 3 (GSK-3) could possibly be inhibited upon phosphorylation by Akt, which leads to enhance of glycogen synthesis. GSK3 can also be concerned in Wnt signaling cascade, so Akt is likely to be additionally implicated within the Wnt pathway.
Its position in HCV induced steatosis is unknown.[citation needed]
Lysosomal biogenesis and autophagy[edit]
Akt regulates TFEB, a grasp controller of lysosomal biogenesis,[24] by direct phosphorylation at serine 467.[25] Phosphorylated TFEB is excluded from the nucleus and fewer energetic.[25] Pharmacological inhibition of Akt promotes nuclear translocation of TFEB, lysosomal biogenesis and autophagy.[25]
Angiogenesis[edit]
Akt1 has additionally been implicated in angiogenesis and tumor growth. Though deficiency of Akt1 in mice inhibited physiological angiogenesis, it enhanced pathological angiogenesis and tumor progress related to matrix abnormalities in pores and skin and blood vessels.[26][27]
Medical relevance[edit]
Akt is related to tumor cell survival, proliferation, and invasiveness. The activation of Akt can also be one of the vital frequent alterations noticed in human most cancers and tumor cells. Tumor cells which have continually energetic Akt could rely upon Akt for survival.[28] Due to this fact, understanding Akt and its pathways is essential for the creation of higher therapies to deal with most cancers and tumor cells. A mosaic-activating mutation (c. 49G→A, p.Glu17Lys) in AKT1 is related to the Proteus Syndrome, which causes overgrowth of pores and skin, connective tissue, mind and different tissues.[29]
AKT inhibitors[edit]
Due to the Akt features above, Akt inhibitors could deal with cancers reminiscent of neuroblastoma. Some Akt inhibitors have undergone scientific trials. In 2007 VQD-002 had a section I trial.[30]
In 2010 Perifosine reached section II.[31] but it surely failed section III in 2012.
Miltefosine is accredited for leishmaniasis and below investigation for different indications together with HIV.
AKT is now considered the “key” for cell entry by HSV-1 and HSV-2 (herpes virus: oral and genital, respectively). Intracellular calcium launch by the cell permits for entry by the herpes virus; the virus prompts AKT, which in flip causes the discharge of calcium. Treating the cells with AKT inhibitors earlier than virus publicity results in a considerably decrease price of an infection.[32]
MK-2206 reported section 1 outcomes for superior strong tumors in 2011,[33] and subsequently has undergone quite a few section II research for all kinds of most cancers sorts.[34]
In 2013 AZD5363 reported section I outcomes concerning strong tumors.[35] with a research of AZD5363 with olaparib reporting in 2016.[36]
Ipatasertib is in section II trials for breast most cancers.[37]
Decreased AKT could cause deleterious results[edit]
AKT activation is related to many malignancies; nonetheless, a analysis group from Massachusetts Normal Hospital and Harvard College unexpectedly noticed a converse position for AKT and one in every of its downstream effector FOXOs in acute myeloid leukemia (AML). They claimed that low ranges of AKT exercise related to elevated ranges of FOXOs are required to keep up the perform and immature state of leukemia-initiating cells (LICs). FOXOs are energetic, implying lowered Akt exercise, in ∼40% of AML affected person samples no matter genetic subtype; and both activation of Akt or compound deletion of FoxO1/3/4 lowered leukemic cell progress in a mouse mannequin.[38]
Hyperactivation of AKT could cause deleterious results[edit]
Two research present that AKT1 is concerned in Juvenile Granulosa Cell tumors (JGCT). In-frame duplications within the pleckstrin-homology area (PHD) of the protein have been discovered in additional than 60% of JGCTs occurring in women below 15 years of age. The JGCTs with out duplications carried level mutations affecting extremely conserved residues. The mutated proteins carrying the duplications displayed a non-wild-type subcellular distribution, with a marked enrichment on the plasma membrane. This led to a hanging diploma of AKT1 activation demonstrated by a powerful phosphorylation stage and corroborated by reporter assays.[39]
Evaluation by RNA-Seq pinpointed a collection of differentially expressed genes, concerned in cytokine and hormone signaling and cell division-related processes. Additional analyses pointed to a attainable dedifferentiation course of and instructed that a lot of the transcriptomic dysregulations is likely to be mediated by a restricted set of transcription components perturbed by AKT1 activation. These outcomes incriminate somatic mutations of AKT1 as main in all probability driver occasions within the pathogenesis of JGCTs.[40]
See additionally[edit]
“protein kinase b”