Protein kinase B - Wikipedia, the free encyclopedia
http://en.wikipedia.org/wiki/Protein_kinase_B
Protein kinase B
From Wikipedia, the free encyclopedia
Protein kinase B (PKB), also known as Akt, is a serine/threonine-specific protein kinase that
plays a key role in multiple cellular processes such as glucose metabolism, apoptosis, cell
proliferation, transcription and cell migration.
AKT1
Contents
1 Family members
2 Name
Ribbon Representation of crystal structure of
Akt-1-inhibitor complexes.[1]
3 Regulation
Identifiers
3.1 Binding phospholipids
3.2 Phosphorylation
Symbol AKT1
3.3 Ubiquitination
Entrez 207 (https://www.ncbi.nlm.nih.gov
/gene?cmd=retrieve&dopt=default&
3.4 Lipid phosphatases and PIP3
3.5 Protein phosphatases
4 Function
4.1 Cell survival
4.2 Cell Cycle
list_uids=207&rn=1)
HUGO 391 (http://www.genenames.org
/data/hgnc_data.php?hgnc_id=391)
OMIM 164730 (http://www.omim.org/164730)
RefSeq NM_005163 (https://genome.ucsc.edu
4.3 Metabolism
/cgi-bin/hgTracks?Submit=Submit&
4.4 Angiogenesis
position=NM_005163&rn=1)
5 Clinical relevance
UniProt P31749 (http://www.uniprot.org/uniprot
/P31749)
5.1 AKT Inhibitors
Other data
5.2 Decreased AKT Can Cause Deleterious Effects
6 See also
7 References
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Locus
Chr. 14 q32.32-32.33 (http://omim.org
/search?index=geneMap&
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Protein kinase B - Wikipedia, the free encyclopedia
http://en.wikipedia.org/wiki/Protein_kinase_B
8 Further reading
search=14q32.32)
9 External links
AKT2
Family members
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. Mouse
model with complete deletion of Akt1 manifests growth retardation and increased
spontaneous apoptosis in tissues such as testes and thymus.[3] 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.[4]
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.[5]
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.[6]
Crystal structure of Akt-2-inhibitor complexes.[2]
Identifiers
Symbol AKT2
Entrez 208 (https://www.ncbi.nlm.nih.gov
/gene?cmd=retrieve&dopt=default&
list_uids=208&rn=1)
HUGO 392 (http://www.genenames.org
/data/hgnc_data.php?hgnc_id=392)
OMIM 164731 (http://www.omim.org/164731)
RefSeq NM_001626 (https://genome.ucsc.edu
/cgi-bin/hgTracks?Submit=Submit&
position=NM_001626&rn=1)
Name
UniProt P31751 (http://www.uniprot.org/uniprot
/P31751)
The name Akt does not refer to its function. The "Ak" in Akt was a temporary classification
name for a mouse bred and maintained by Jacob Furth that developed spontaneous thymic
lymphomas. The "t" stands for 'thymoma'; 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.
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Other data
Locus
Chr. 19 q13.1-13.2 (http://omim.org
/search?index=geneMap&
search=19q13.1)
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Regulation
AKT3
Identifiers
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).[7] 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.
Symbol AKT3
Entrez 10000 (https://www.ncbi.nlm.nih.gov
/gene?cmd=retrieve&dopt=default&
list_uids=10000&rn=1)
HUGO 393 (http://www.genenames.org
/data/hgnc_data.php?hgnc_id=393)
OMIM 611223 (http://www.omim.org/611223)
RefSeq NM_181690 (https://genome.ucsc.edu
/cgi-bin/hgTracks?Submit=Submit&
position=NM_181690&rn=1)
UniProt Q9Y243 (http://www.uniprot.org/uniprot
/Q9Y243)
Phosphorylation
Other data
Locus Chr. 1 q43-44 (http://omim.org
Once correctly positioned at the membrane via binding of PIP3, Akt can then be
/search?index=geneMap&search=1q43)
phosphorylated by its activating kinases, phosphoinositide dependent kinase 1 (PDPK1 at
threonine 308) and the mammalian target of rapamycin complex 2 (mTORC2 at serine
473),[8][9] first by 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 (e.g. mTOR) via its kinase activity.
Besides being a downstream effector of PI 3-kinases, Akt can also be activated in a PI 3-kinase-independent manner.[10] 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.[10]
Studies have suggested that cAMP-elevating agents could also activate Akt through protein kinase A (PKA) in the presence of insulin.[11]
Ubiquitination
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Akt is normally phosphorylated at position T450 in the turn motif when Akt is translated. If Akt is not phosphorylated at this position, Akt does
not fold in the right way. The T450-non-phosphorylated misfolded Akt is ubiquitinated and degraded by the proteasome. Akt is also
phosphorylated at T308 and S473 during IGF-1 response, and the resulting polyphosphorylated Akt is ubiquitinated partly by E3 ligase NEDD4.
Most of the ubiquitinated-phosphorylated-Akt is degraded by the proteasome, while a small amount of phosphorylated-Akt translocates to the
nucleus in a ubiquitination-dependent way to phosphorylate its substrate. A cancer-derived mutant Akt (E17K) is more readily ubiquitinated and
phosphorylated than the wild type Akt. The ubiquitinated-phosphorylated-Akt (E17K) translocates more efficiently to the nucleus than the wild
type Akt. This mechanism may contribute to E17K-Akt-induced cancer in humans.[12]
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.[13] PTEN acts as a phosphatase to dephosphorylate PIP3 back to PIP2. 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
inositol phosphatases dephosphorylate PIP3 to form PIP2.
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[14] 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,[15] which makes BAD dissociate from the Bcl-2/Bcl-X complex and lose the pro-apoptotic function.[16]
Akt could also activate NF-κB via regulating IκB kinase (IKK), thus result in transcription of pro-survival genes.[17]
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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[18] and G2[19] 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 increase 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.
Overview of signal transduction
pathways involved in apoptosis.
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.[20][21]
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.[22] 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.[23]
AKT Inhibitors
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.[24] In 2010 Perifosine reached phase II.[25] but it failed phase III in 2012.
Miltefosine is approved for leishmaniasis and under investigation for other indications including HIV.
AKT is now thought to be the "key" for cell entry by HSV-1 and HSV-2 (herpes virus: oral and genital, respectively). Intracellular calcium
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release by the cell allows for entry by the herpes virus; the virus activates AKT, 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.[26]
In 2013 AZD5363 reported phase I results re solid tumors.[27]
Decreased AKT Can Cause Deleterious Effects
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 leukemiainitiating 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.[28]
See also
Akt/PKB signaling pathway
Discovery and development of mTOR inhibitors
PI3K/AKT/mTOR pathway
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25. ^ Ghobrial IM, Roccaro A, Hong F, Weller E, Rubin N, Leduc R,
http://en.wikipedia.org/wiki/Protein_kinase_B
26. ^ Cheshenko N, Trepanier JB, Stefanidou M, Buckley N, Gonzalez P,
Rourke M, Chuma S, Sacco A, Jia X, Azab F, Azab AK, Rodig S,
Jacobs W, Herold BC (March 2013). "HSV activates Akt to trigger
Warren D, Harris B, Varticovski L, Sportelli P, Leleu X, Anderson KC,
calcium release and promote viral entry: novel candidate target for
Richardson PG (February 2010). "Clinical and translational studies of a
treatment and suppression". FASEB J. 27 (7): 2584–99.
phase II trial of the novel oral Akt inhibitor perifosine in relapsed or
doi:10.1096/fj.12-220285 (http://dx.doi.org/10.1096%2Ffj.12-220285).
relapsed/refractory Waldenstrom's macroglobulinemia"
PMID 23507869 (https://www.ncbi.nlm.nih.gov/pubmed/23507869).
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2885252). Clin.
Lay summary (http://www.sci-news.com/medicine/article00981.html) –
Cancer Res. 16 (3): 1033–41. doi:10.1158/1078-0432.CCR-09-1837
Sci-News.
(http://dx.doi.org/10.1158%2F1078-0432.CCR-09-1837).
27. ^ AKT inhibitor AZD5363 well tolerated, yielded partial response in
PMC 2885252 (https://www.ncbi.nlm.nih.gov/pmc/articles
patients with advanced solid tumors (http://medicalxpress.com
/PMC2885252). PMID 20103671 (https://www.ncbi.nlm.nih.gov
/news/2013-04-akt-inhibitor-azd5363-tolerated-yielded.html)
/pubmed/20103671).
28. ^ Sykes SM, Lane SW, Bullinger L, Kalaitzidis D, Yusuf R, Saez B,
Ferraro F, Mercier F, Singh H, Brumme KM, Acharya SS, Scholl C,
Schöll C, Tothova Z, Attar EC, Fröhling S, DePinho RA, Armstrong
SA, Gilliland DG, Scadden DT (September 2011). "AKT/FOXO
signaling enforces reversible differentiation blockade in myeloid
leukemias". Cell 146 (5): 697–708. doi:10.1016/j.cell.2011.07.032
(http://dx.doi.org/10.1016%2Fj.cell.2011.07.032). PMID 21884932
(https://www.ncbi.nlm.nih.gov/pubmed/21884932).
Further reading
Los M, Maddika S, Erb B, Schulze-Osthoff K (May 2009). "Switching Akt: from survival signaling to deadly response"
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2954189). BioEssays 31 (5): 492–5. doi:10.1002/bies.200900005 (http://dx.doi.org
/10.1002%2Fbies.200900005). PMC 2954189 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2954189). PMID 19319914
(https://www.ncbi.nlm.nih.gov/pubmed/19319914).
Quaresma AJ, Sievert R, Nickerson JA (2013). "Regulation of mRNA export by the PI3 kinase/AKT signal transduction pathway."
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3623641). Mol. Biol. Cell. April (8): 1208–21. doi:10.1091/mbc.E12-06-0450
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Protein kinase B - Wikipedia, the free encyclopedia
http://en.wikipedia.org/wiki/Protein_kinase_B
(http://dx.doi.org/10.1091%2Fmbc.E12-06-0450). PMC 3623641 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3623641).
PMID 23427269 (https://www.ncbi.nlm.nih.gov/pubmed/23427269).
External links
Proto-Oncogene Proteins c-akt (https://www.nlm.nih.gov/cgi/mesh/2011/MB_cgi?mode=&term=Proto-Oncogene+Proteins+c-akt) at the
US National Library of Medicine Medical Subject Headings (MeSH)
Retrieved from "http://en.wikipedia.org/w/index.php?title=Protein_kinase_B&oldid=630687552"
Categories: Genes on chromosome 14 Genes on chromosome 19 Genes on chromosome 1 Cell signaling Signal transduction EC 2.7.11
Protein kinases
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