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Gene Review

Akt1  -  CG4006 gene product from transcript CG4006-RE

Drosophila melanogaster

Synonyms: AKT, AKT/PKB, AKT1, Akt, Akt/PKB, ...
 
 
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Disease relevance of Akt1

 

High impact information on Akt1

  • A mutant form of AKT lacking the HM phosphorylation site displayed comparable activity [5].
  • Growth inhibition is associated with a reduction in S6K but not PKB/Akt activity [6].
  • Together, genetic and biochemical analysis places Scylla/Charybdis downstream of PKB and upstream of TSC [6].
  • Tsc2 is not a critical target of Akt during normal Drosophila development [2].
  • The direct mechanism by which the serine/threonine kinase Akt (also known as protein kinase B (PKB)) regulates cell growth is unknown [7].
 

Biological context of Akt1

  • BACKGROUND: The activation of protein kinase B (PKB, also known as c-Akt) is stimulated by insulin or growth factors and results from its phosphorylation at Thr308 and Ser473 [8].
  • Dakt1 was mapped to Drosophila chromosome 3R 89BC [9].
  • The SH2-like Akt homology (AH) domain of c-akt is present in multiple copies in the genome of vertebrate and invertebrate eucaryotes. Cloning and characterization of the Drosophila melanogaster c-akt homolog Dakt1 [9].
  • The Akt proto-oncogene encodes a serine-threonine protein kinase whose carboxyterminal catalytic domain is closely related to the catalytic domains of all the known members of the protein kinase C (PKC) family [9].
  • This in turn finely tunes activation of Akt1, a process essential for proper morphogenesis of the light-gathering organelle, consisting of a stack of F-actin rich microvilli within the apical membrane [10].
 

Anatomical context of Akt1

  • The P3k oncoprotein [homolog of the catalytic subunit p110alpha of class 1A phosphoinositide 3-kinase (PI3K)] and its downstream effector Akt induce oncogenic transformation in cultures of chicken embryo fibroblasts (CEF) [11].
  • In this study, we show that elevated signaling through PI3K and Akt can prevent developmentally controlled death in the salivary glands of the fruit fly [12].
  • Phosphatidylinositol 3-kinase and Akt nonautonomously promote perineurial glial growth in Drosophila peripheral nerves [4].
  • Akt directly stimulates the activity of translation initiation factors and upregulates ribosome biogenesis [13].
  • In vivo activation of PKB/AKT necessitates its recruitment to the cell membrane mediated by the N-terminal pleckstrin homology (PH) domain [14].
 

Associations of Akt1 with chemical compounds

  • Akt, however, differs from PKC in its N-terminal region which contains a domain related distantly to the SH2 domain of cytoplasmic tyrosine kinases and other signalling proteins, which we have named Akt homology (AH) domain [9].
  • Insulin-induced Drosophila S6 kinase activation requires phosphoinositide 3-kinase and protein kinase B [15].
  • Here we show that genetic manipulation of the phosphoinositide-3-OH-kinase-dependent serine/threonine protein kinase Akt (protein kinase B) during development of the Drosophila imaginal disc affects cell and organ size in an autonomous manner [16].
  • The insulin-induced activations of dERK and dAKT were blocked by LY294002, dPTEN, and by an AKT inhibitor, indicating involvement of dPI3K and dAKT in the insulin-induced dERK and dAKT activations [17].
  • We also observed impairment of PI3K/Akt signaling in the fly parkin model of PD, hinting at a common molecular event in the pathogenesis of PD [18].
  • We conclude that isoforms of PP2A-B' can act as subcellular-compartment-specific regulators of PI3-kinase/PTEN/Akt kinase signalling and IIS, potentially providing new targets for modulating individual subcellular pools of activated Akt in insulin-linked disease [19].
 

Regulatory relationships of Akt1

  • PDK1 regulates growth through Akt and S6K in Drosophila [20].
  • Akt is regulated by phosphatidylinositol 3-OH kinase (PI3'K) signaling and has shown to be hyperactivated through the loss of the PTEN tumor suppressor [21].
  • FOXO activity is inhibited by the insulin effector kinase Akt; we show that Akt activation is systemically reduced as a result of M. marinum infection [22].
 

Other interactions of Akt1

  • This functional interaction between dPDK-1 and Dakt1 was further confirmed through genetic analyses in Drosophila [23].
  • The conserved PI3'K/PTEN/Akt signaling pathway regulates both cell size and survival in Drosophila [21].
  • We also show that Drosophila AKT (DAKT) activation depends on the insulin receptor substrate, CHICO (IRS1-4) [24].
  • Epistasis experiments and a variety of biochemical studies that followed have indicated a critical function for these proteins in the highly conserved PI-3-kinase-Akt-mTOR signalling pathway [25].
  • Applying a combined genetic and biochemical approach has led to the identification of a new protein kinase B/Akt target, the transcription factor Trachealess [26].
 

Analytical, diagnostic and therapeutic context of Akt1

References

  1. The cytohesin Steppke is essential for insulin signalling in Drosophila. Fuss, B., Becker, T., Zinke, I., Hoch, M. Nature (2006) [Pubmed]
  2. Tsc2 is not a critical target of Akt during normal Drosophila development. Dong, J., Pan, D. Genes Dev. (2004) [Pubmed]
  3. Genetic analysis of protein kinase B (AKT) in Drosophila. Staveley, B.E., Ruel, L., Jin, J., Stambolic, V., Mastronardi, F.G., Heitzler, P., Woodgett, J.R., Manoukian, A.S. Curr. Biol. (1998) [Pubmed]
  4. Phosphatidylinositol 3-kinase and Akt nonautonomously promote perineurial glial growth in Drosophila peripheral nerves. Lavery, W., Hall, V., Yager, J.C., Rottgers, A., Wells, M.C., Stern, M. J. Neurosci. (2007) [Pubmed]
  5. Re-evaluating AKT regulation: role of TOR complex 2 in tissue growth. Hietakangas, V., Cohen, S.M. Genes Dev. (2007) [Pubmed]
  6. The hypoxia-induced paralogs Scylla and Charybdis inhibit growth by down-regulating S6K activity upstream of TSC in Drosophila. Reiling, J.H., Hafen, E. Genes Dev. (2004) [Pubmed]
  7. Akt regulates growth by directly phosphorylating Tsc2. Potter, C.J., Pedraza, L.G., Xu, T. Nat. Cell Biol. (2002) [Pubmed]
  8. 3-Phosphoinositide-dependent protein kinase-1 (PDK1): structural and functional homology with the Drosophila DSTPK61 kinase. Alessi, D.R., Deak, M., Casamayor, A., Caudwell, F.B., Morrice, N., Norman, D.G., Gaffney, P., Reese, C.B., MacDougall, C.N., Harbison, D., Ashworth, A., Bownes, M. Curr. Biol. (1997) [Pubmed]
  9. The SH2-like Akt homology (AH) domain of c-akt is present in multiple copies in the genome of vertebrate and invertebrate eucaryotes. Cloning and characterization of the Drosophila melanogaster c-akt homolog Dakt1. Franke, T.F., Tartof, K.D., Tsichlis, P.N. Oncogene (1994) [Pubmed]
  10. Regulated and polarized PtdIns(3,4,5)P3 accumulation is essential for apical membrane morphogenesis in photoreceptor epithelial cells. Pinal, N., Goberdhan, D.C., Collinson, L., Fujita, Y., Cox, I.M., Wilson, C., Pichaud, F. Curr. Biol. (2006) [Pubmed]
  11. Proteasomal degradation of the FoxO1 transcriptional regulator in cells transformed by the P3k and Akt oncoproteins. Aoki, M., Jiang, H., Vogt, P.K. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  12. FOXO-independent suppression of programmed cell death by the PI3K/Akt signaling pathway in Drosophila. Liu, Y., Lehmann, M. Dev. Genes Evol. (2006) [Pubmed]
  13. The Akt of translational control. Ruggero, D., Sonenberg, N. Oncogene (2005) [Pubmed]
  14. Mutations of the PH domain of protein kinase B (PKB/AKT) are absent in human epidermal skin tumors. Waldmann, V., Wacker, J. Dermatology (Basel) (2001) [Pubmed]
  15. Insulin-induced Drosophila S6 kinase activation requires phosphoinositide 3-kinase and protein kinase B. Lizcano, J.M., Alrubaie, S., Kieloch, A., Deak, M., Leevers, S.J., Alessi, D.R. Biochem. J. (2003) [Pubmed]
  16. Cell-autonomous regulation of cell and organ growth in Drosophila by Akt/PKB. Verdu, J., Buratovich, M.A., Wilder, E.L., Birnbaum, M.J. Nat. Cell Biol. (1999) [Pubmed]
  17. Drosophila PI3 kinase and Akt involved in insulin-stimulated proliferation and ERK pathway activation in Schneider cells. Kim, S.E., Cho, J.Y., Kim, K.S., Lee, S.J., Lee, K.H., Choi, K.Y. Cell. Signal. (2004) [Pubmed]
  18. Inactivation of Drosophila DJ-1 leads to impairments of oxidative stress response and phosphatidylinositol 3-kinase/Akt signaling. Yang, Y., Gehrke, S., Haque, M.E., Imai, Y., Kosek, J., Yang, L., Beal, M.F., Nishimura, I., Wakamatsu, K., Ito, S., Takahashi, R., Lu, B. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  19. The protein phosphatase PP2A-B' subunit Widerborst is a negative regulator of cytoplasmic activated Akt and lipid metabolism in Drosophila. Vereshchagina, N., Ramel, M.C., Bitoun, E., Wilson, C. J. Cell. Sci. (2008) [Pubmed]
  20. PDK1 regulates growth through Akt and S6K in Drosophila. Rintelen, F., Stocker, H., Thomas, G., Hafen, E. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  21. The conserved PI3'K/PTEN/Akt signaling pathway regulates both cell size and survival in Drosophila. Scanga, S.E., Ruel, L., Binari, R.C., Snow, B., Stambolic, V., Bouchard, D., Peters, M., Calvieri, B., Mak, T.W., Woodgett, J.R., Manoukian, A.S. Oncogene (2000) [Pubmed]
  22. Akt and foxo Dysregulation Contribute to Infection-Induced Wasting in Drosophila. Dionne, M.S., Pham, L.N., Shirasu-Hiza, M., Schneider, D.S. Curr. Biol. (2006) [Pubmed]
  23. Drosophila phosphoinositide-dependent kinase-1 regulates apoptosis and growth via the phosphoinositide 3-kinase-dependent signaling pathway. Cho, K.S., Lee, J.H., Kim, S., Kim, D., Koh, H., Lee, J., Kim, C., Kim, J., Chung, J. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  24. Use of double-stranded RNA interference in Drosophila cell lines to dissect signal transduction pathways. Clemens, J.C., Worby, C.A., Simonson-Leff, N., Muda, M., Maehama, T., Hemmings, B.A., Dixon, J.E. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  25. Tuberous sclerosis: from tubers to mTOR. Kwiatkowski, D.J. Ann. Hum. Genet. (2003) [Pubmed]
  26. Trachealess--a new transcription factor target for PKB/Akt. Downward, J., Leevers, S.J. Dev. Cell (2001) [Pubmed]
 
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