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v-akt murine thymoma viral oncogene homolog 1
Identifiers
Symbol AKT1
Entrez 207
HUGO 391
OMIM 164730
RefSeq NM_005163
UniProt P31749
Other data
Locus Chr. 14 q32.32-32.33
v-akt murine thymoma viral oncogene homolog 2
Identifiers
Symbol AKT2
Entrez 208
HUGO 392
OMIM 164731
RefSeq NM_001626
UniProt P31751
Other data
Locus Chr. 19 q13.1-13.2
v-akt murine thymoma viral oncogene homolog 3 (protein kinase B, gamma)
Identifiers
Symbol AKT3
Entrez 10000
HUGO 393
RefSeq NM_181690
UniProt Q9Y243
Other data
Locus Chr. 1 q43-44

AKT protein family, which members are also called protein kinases B (PKB) plays an important role in mammalian cellular signaling.

Contents

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 serine/threonine-specific protein kinase family (EC 2.7.11.1).

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.[1] 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.[2]

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 resistance), again consistent with the idea that Akt2 is more specific for the insulin receptor signaling pathway.[3]

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.[4]

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.

Regulation

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 phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3 aka PIP3) or phosphatidylinositol (3,4)-bisphosphate (PtdIns(3,4)P2 aka PI(3,4)P2). This is useful for control of cellular signaling because the di-phosphorylated phosphoinositide PtdIns(4,5)P2 is only phosphorylated by the family of enzymes, PI 3-kinases (phosphoinositide 3-kinase 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 kinase such as the insulin receptor. Once activated, PI 3-kinases phosphorylates PtdIns(4,5)P2 to form PtdIns(3,4,5)P3.

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 (MAPKAPK2) 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.[5 ]

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 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.[6] 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 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, 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[7] 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

Overview of signal transduction pathways involved in apoptosis.

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,[8] which makes BAD dissociate from the Bcl-2/Bcl-X complex and lose the pro-apoptotic function.[9] Akt could also activate NF-κB via regulating IκB kinase (IKK), thus result in transcription of pro-survival genes.[10]

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[11] and G2[12] 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.[13][14]

References

  1. ^ Staal SP, Hartley JW, Rowe WP (July 1977). "Isolation of transforming murine leukemia viruses from mice with a high incidence of spontaneous lymphoma". Proc. Natl. Acad. Sci. U.S.A. 74 (7): 3065–7. PMID 197531.  
  2. ^ Staal SP (July 1987). "Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: amplification of AKT1 in a primary human gastric adenocarcinoma". Proc. Natl. Acad. Sci. U.S.A. 84 (14): 5034–7. PMID 3037531. PMC 305241. http://www.pnas.org/content/84/14/5034.abstract.  
  3. ^ Garofalo RS, Orena SJ, Rafidi K, Torchia AJ, Stock JL, Hildebrandt AL, Coskran T, Black SC, Brees DJ, Wicks JR, McNeish JD, Coleman KG (July 2003). "Severe diabetes, age-dependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKB beta". J. Clin. Invest. 112 (2): 197–208. doi:10.1172/JCI16885. PMID 12843127.  
  4. ^ Yang ZZ, Tschopp O, Baudry A, Dümmler B, Hynx D, Hemmings BA (April 2004). "Physiological functions of protein kinase B/Akt". Biochem. Soc. Trans. 32 (Pt 2): 350–4. doi:10.1042/ (inactive 2009-01-05). PMID 15046607.  
  5. ^ "Akt signaling pathway". Product Pathways. Cell Signaling Technology, Inc.. http://www.cellsignal.com/pathways/akt-signaling.jsp. Retrieved 2009-01-05.  
  6. ^ Cooper, Geoffrey M. (2000). "Figure 15.37: PTEN and PI3K". The cell: a molecular approach. Washington, D.C: ASM Press. ISBN 0-87893-106-6. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=cooper.figgrp.2669.  
  7. ^ Song G, Ouyang G, Bao S (2005). "The activation of Akt/PKB signaling pathway and cell survival". J. Cell. Mol. Med. 9 (1): 59–71. doi:10.1111/j.1582-4934.2005.tb00337.x. PMID 15784165.  
  8. ^ Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P (2002). "Figure 15-60: BAD phosphorylation by Akt". Molecular biology of the cell. New York: Garland Science. ISBN 0-8153-3218-1. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mboc4.figgrp.2865.  
  9. ^ Lodish H, Berk A, Zipursky LS, Matsudaira P, Baltimore D, Darnell J (1999). "Figure 23-50: BAD interaction with Bcl-2". Molecular cell biology. New York: Scientific American Books. ISBN 0-7167-3136-3. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mcb.figgrp.6902.  
  10. ^ Faissner A, Heck N, Dobbertin A, Garwood J (2006). "DSD-1-Proteoglycan/Phosphacan and receptor protein tyrosine phosphatase-beta isoforms during development and regeneration of neural tissues". Adv. Exp. Med. Biol. 557: 25–53, Figure 2: regulation of NF-kB. doi:10.1007/0-387-30128-3_3. PMID 16955703. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=eurekah.figgrp.997.  
  11. ^ Ramaswamy S, Nakamura N, Vazquez F, Batt DB, Perera S, Roberts TM, Sellers WR (March 1999). "Regulation of G1 progression by the PTEN tumor suppressor protein is linked to inhibition of the phosphatidylinositol 3-kinase/Akt pathway". Proc. Natl. Acad. Sci. U.S.A. 96 (5): 2110–5. doi:10.1073/pnas.96.5.2110. PMID 10051603.  
  12. ^ Kandel ES, Skeen J, Majewski N, Di Cristofano A, Pandolfi PP, Feliciano CS, Gartel A, Hay N (November 2002). "Activation of Akt/protein kinase B overcomes a G(2)/m cell cycle checkpoint induced by DNA damage". Mol. Cell. Biol. 22 (22): 7831–41. doi:10.1128/MCB.22.22.7831-7841.2002. PMID 12391152.  
  13. ^ Chen J, Somanath PR, Razorenova O, Chen WS, Hay N, Bornstein P, Byzova TV (November 2005). "Akt1 regulates pathological angiogenesis, vascular maturation and permeability in vivo". Nat. Med. 11 (11): 1188–96. doi:10.1038/nm1307. PMID 16227992.  
  14. ^ Somanath PR, Razorenova OV, Chen J, Byzova TV (March 2006). "Akt1 in endothelial cell and angiogenesis". Cell Cycle 5 (5): 512–8. PMID 16552185. PMC 1569947. http://www.landesbioscience.com/journals/cc/article/2538/.  

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








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