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AKT1  -  v-akt murine thymoma viral oncogene homolog 1

Homo sapiens

 
 
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Disease relevance of AKT1

  • A survey of 225 human tumors for changes involving AKT1 led to the discovery of a 20-fold amplification of this gene in one of the five gastric adenocarcinomas tested [1].
  • Confocal microscopy performed on transfected human breast cancer cells showed that unlike AKT1, AKT2 protein predominantly localized adjacent to the collagen IV matrix during cellular attachment [2].
  • Amplification and overexpression of AKT1 was detected in a single case of gliosarcoma [3].
  • Lentivirus constructs were used to stably express constitutively active AKT1 or AKT2 in GIST cells to study the role of AKT signaling in metabolism and cell survival [4].
  • Because impaired insulin signalling is a major hallmark of Type II (non-insulin-dependent) diabetes mellitus, we considered whether the AKT1 gene could be a candidate gene involved in susceptibility of this condition [5].
  • In this review, the role of AKT in thyroid cancer development and progression are discussed with a focus on areas of current debate in the literature [6].
  • Our results further showed that AKT1 induced lung cancer cells to become resistant to CDDP through the mammalian target of the rapamycin (mTOR) signaling pathway [7].
 

Psychiatry related information on AKT1

 

High impact information on AKT1

 

Chemical compound and disease context of AKT1

 

Biological context of AKT1

  • The AKT1, AKT2, and AKT3 kinases have emerged as critical mediators of signal transduction pathways downstream of activated tyrosine kinases and phosphatidylinositol 3-kinase [23].
  • Two human homologues of the v-akt oncogene, AKT1 and AKT2, were cloned [1].
  • Finally, the LCLs in the lowest apoptotic response group have the highest concentration of AKT1 protein and all harbor a haplotype in AKT1 that is present in Caucasians but absent in African Americans [24].
  • The assay is capable of detecting significant effects of SNPs in two genes, MDM2 and AKT1, whose products are involved in controlling the p53 pathway and cellular response to DNA damage, suggesting that these data and this assay can be used to identify novel SNPs in other genes whose products impact the cellular response to radiation [24].
  • Furthermore, the expression of activated AKT1 inhibits MLK3-mediated cell death in a manner dependent on serine 674 phosphorylation [25].
 

Anatomical context of AKT1

 

Associations of AKT1 with chemical compounds

  • Importantly, expression of constitutively active AKT1 or AKT2 does not rescue cells from the imatinib-mediated apoptosis although glucose uptake was not blocked, suggesting that the potential therapeutic effect of imatinib is independent of AKT activity and glucose deprivation [4].
  • AIMS/HYPOTHESIS: AKT1, a serine/threonine protein kinase, is an important downstream target of the insulin-signalling pathway, with both anti-apoptotic and peripheral metabolic effects [5].
  • The EGFR kinase inhibitor PD158780 reduced the constitutive phosphorylation of the receptor and Erk but not that of AKT1 [31].
  • Our results indicate that the combination of cyclosporin A and Taxol is effective in the reversal of Taxol resistance through the inhibition of PI3 kinase-AKT1 pathway [32].
  • In vitro, endothelial vasorelaxations to acetylcholine, isoproterenol, and insulin were blunted in control carotids from SHR compared with WKY rats, and human AKT1 overexpression corrected these responses [30].
  • The association of AR with Akt1 was inhibited by the anti-androgen, bicalutamide, but was not affected by inhibition of phosphoinositide 3-kinase (PI3K) [33].
  • Ca(2+).CaM competes with phosphatidylinositol 3,4,5-trisphophate for interaction with the PH domain of human AKT1 [34].
 

Physical interactions of AKT1

  • Altogether, our data demonstrate that Akt1 participates in a negative regulatory feedback loop by interacting with the JIP1 scaffold protein [35].
  • Here we provide evidence that PKC theta is physically and functionally coupled to Akt1 in this signaling pathway [36].
  • In this manner, RAC is closely juxtaposed to the cell membrane of the target cell and is anchored in this position via binding of the remaining antigen-combining site to p40 prostate restricted antigen [37].
  • PKB/Akt interacts with inosine-5' monophosphate dehydrogenase through its pleckstrin homology domain [38].
  • A yeast-based two-hybrid system was employed which identified inosine-5' monophosphate dehydrogenase (IMPDH) type II as specifically interacting with PKB/Akts PH domain [38].
 

Enzymatic interactions of AKT1

 

Regulatory relationships of AKT1

 

Other interactions of AKT1

 

Analytical, diagnostic and therapeutic context of AKT1

References

  1. Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: amplification of AKT1 in a primary human gastric adenocarcinoma. Staal, S.P. Proc. Natl. Acad. Sci. U.S.A. (1987) [Pubmed]
  2. Overexpression of AKT2/protein kinase Bbeta leads to up-regulation of beta1 integrins, increased invasion, and metastasis of human breast and ovarian cancer cells. Arboleda, M.J., Lyons, J.F., Kabbinavar, F.F., Bray, M.R., Snow, B.E., Ayala, R., Danino, M., Karlan, B.Y., Slamon, D.J. Cancer Res. (2003) [Pubmed]
  3. Genetic alterations and aberrant expression of genes related to the phosphatidyl-inositol-3'-kinase/protein kinase B (Akt) signal transduction pathway in glioblastomas. Knobbe, C.B., Reifenberger, G. Brain Pathol. (2003) [Pubmed]
  4. Therapeutic effect of imatinib in gastrointestinal stromal tumors: AKT signaling dependent and independent mechanisms. Tarn, C., Skorobogatko, Y.V., Taguchi, T., Eisenberg, B., von Mehren, M., Godwin, A.K. Cancer Res. (2006) [Pubmed]
  5. Isolation and characterization of the human AKT1 gene, identification of 13 single nucleotide polymorphisms (SNPs), and their lack of association with Type II diabetes. Matsubara, A., Wasson, J.C., Donelan, S.S., Welling, C.M., Glaser, B., Permutt, M.A. Diabetologia (2001) [Pubmed]
  6. AKT in thyroid tumorigenesis and progression. Shinohara, M., Chung, Y.J., Saji, M., Ringel, M.D. Endocrinology (2007) [Pubmed]
  7. AKT1 amplification regulates cisplatin resistance in human lung cancer cells through the mammalian target of rapamycin/p70S6K1 pathway. Liu, L.Z., Zhou, X.D., Qian, G., Shi, X., Fang, J., Jiang, B.H. Cancer Res. (2007) [Pubmed]
  8. Further evidence for association of variants in the AKT1 gene with schizophrenia in a sample of European sib-pair families. Schwab, S.G., Hoefgen, B., Hanses, C., Hassenbach, M.B., Albus, M., Lerer, B., Trixler, M., Maier, W., Wildenauer, D.B. Biol. Psychiatry (2005) [Pubmed]
  9. Activation of protein kinase B/Akt in the periphery contributes to pain behavior induced by capsaicin in rats. Sun, R., Yan, J., Willis, W.D. Neuroscience (2007) [Pubmed]
  10. The IGF-1/Akt pathway is neuroprotective in Huntington's disease and involves Huntingtin phosphorylation by Akt. Humbert, S., Bryson, E.A., Cordelières, F.P., Connors, N.C., Datta, S.R., Finkbeiner, S., Greenberg, M.E., Saudou, F. Dev. Cell (2002) [Pubmed]
  11. Analysis of a cluster of polymorphisms in AKT1 gene in bipolar pedigrees: a family-based association study. Toyota, T., Yamada, K., Detera-Wadleigh, S.D., Yoshikawa, T. Neurosci. Lett. (2003) [Pubmed]
  12. Akt/GSK3beta serine/threonine kinases: evidence for a signalling pathway mediated by familial Alzheimer's disease mutations. Ryder, J., Su, Y., Ni, B. Cell. Signal. (2004) [Pubmed]
  13. SIN1/MIP1 Maintains rictor-mTOR Complex Integrity and Regulates Akt Phosphorylation and Substrate Specificity. Jacinto, E., Facchinetti, V., Liu, D., Soto, N., Wei, S., Jung, S.Y., Huang, Q., Qin, J., Su, B. Cell (2006) [Pubmed]
  14. Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia. Emamian, E.S., Hall, D., Birnbaum, M.J., Karayiorgou, M., Gogos, J.A. Nat. Genet. (2004) [Pubmed]
  15. mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Majumder, P.K., Febbo, P.G., Bikoff, R., Berger, R., Xue, Q., McMahon, L.M., Manola, J., Brugarolas, J., McDonnell, T.J., Golub, T.R., Loda, M., Lane, H.A., Sellers, W.R. Nat. Med. (2004) [Pubmed]
  16. Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27(Kip1) by PKB/Akt-mediated phosphorylation in breast cancer. Viglietto, G., Motti, M.L., Bruni, P., Melillo, R.M., D'Alessio, A., Califano, D., Vinci, F., Chiappetta, G., Tsichlis, P., Bellacosa, A., Fusco, A., Santoro, M. Nat. Med. (2002) [Pubmed]
  17. PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest. Liang, J., Zubovitz, J., Petrocelli, T., Kotchetkov, R., Connor, M.K., Han, K., Lee, J.H., Ciarallo, S., Catzavelos, C., Beniston, R., Franssen, E., Slingerland, J.M. Nat. Med. (2002) [Pubmed]
  18. Medulloblastoma sensitivity to 17-allylamino-17-demethoxygeldanamycin requires MEK/ERKM. Calabrese, C., Frank, A., Maclean, K., Gilbertson, R. J. Biol. Chem. (2003) [Pubmed]
  19. Gonadotropin-releasing hormone induces apoptosis of prostate cancer cells: role of c-Jun NH2-terminal kinase, protein kinase B, and extracellular signal-regulated kinase pathways. Kraus, S., Levy, G., Hanoch, T., Naor, Z., Seger, R. Cancer Res. (2004) [Pubmed]
  20. Muscarinic receptors mediate phospholipase C-dependent activation of protein kinase B via Ca2+, ErbB3, and phosphoinositide 3-kinase in 1321N1 astrocytoma cells. Tang, X., Batty, I.H., Downes, C.P. J. Biol. Chem. (2002) [Pubmed]
  21. Protein kinase B/Akt regulates coxsackievirus B3 replication through a mechanism which is not caspase dependent. Esfandiarei, M., Luo, H., Yanagawa, B., Suarez, A., Dabiri, D., Zhang, J., McManus, B.M. J. Virol. (2004) [Pubmed]
  22. Differential roles of phosphoinositide-dependent protein kinase-1 and akt1 expression and phosphorylation in breast cancer cell resistance to Paclitaxel, Doxorubicin, and gemcitabine. Liang, K., Lu, Y., Li, X., Zeng, X., Glazer, R.I., Mills, G.B., Fan, Z. Mol. Pharmacol. (2006) [Pubmed]
  23. Activation of AKT kinases in cancer: implications for therapeutic targeting. Bellacosa, A., Kumar, C.C., Di Cristofano, A., Testa, J.R. Adv. Cancer Res. (2005) [Pubmed]
  24. Detection of functional single-nucleotide polymorphisms that affect apoptosis. Harris, S.L., Gil, G., Robins, H., Hu, W., Hirshfield, K., Bond, E., Bond, G., Levine, A.J. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  25. Negative regulation of mixed lineage kinase 3 by protein kinase B/AKT leads to cell survival. Barthwal, M.K., Sathyanarayana, P., Kundu, C.N., Rana, B., Pradeep, A., Sharma, C., Woodgett, J.R., Rana, A. J. Biol. Chem. (2003) [Pubmed]
  26. AKT1 Provides an Essential Survival Signal Required for Differentiation and Stratification of Primary Human Keratinocytes. Thrash, B.R., Menges, C.W., Pierce, R.H., McCance, D.J. J. Biol. Chem. (2006) [Pubmed]
  27. Blockade of AKT activation in prostate cancer cells with a small molecule inhibitor, 9-chloro-2-methylellipticinium acetate (CMEP). Zhang, M., Fang, X., Liu, H., Wang, S., Yang, D. Biochem. Pharmacol. (2007) [Pubmed]
  28. The AKT1 proto-oncogene maps to human chromosome 14, band q32. Staal, S.P., Huebner, K., Croce, C.M., Parsa, N.Z., Testa, J.R. Genomics (1988) [Pubmed]
  29. Automated high content screening for phosphoinositide 3 kinase inhibition using an AKT 1 redistribution assay. Wolff, M., Haasen, D., Merk, S., Kroner, M., Maier, U., Bordel, S., Wiedenmann, J., Nienhaus, G.U., Valler, M., Heilker, R. Comb. Chem. High Throughput Screen. (2006) [Pubmed]
  30. AKT participates in endothelial dysfunction in hypertension. Iaccarino, G., Ciccarelli, M., Sorriento, D., Cipolletta, E., Cerullo, V., Iovino, G.L., Paudice, A., Elia, A., Santulli, G., Campanile, A., Arcucci, O., Pastore, L., Salvatore, F., Condorelli, G., Trimarco, B. Circulation (2004) [Pubmed]
  31. Spontaneous activation and signaling by overexpressed epidermal growth factor receptors in glioblastoma cells. Thomas, C.Y., Chouinard, M., Cox, M., Parsons, S., Stallings-Mann, M., Garcia, R., Jove, R., Wharen, R. Int. J. Cancer (2003) [Pubmed]
  32. Reversal of Taxol resistance in hepatoma by cyclosporin A: involvement of the PI-3 kinase-AKT 1 pathway. Lin, H.L., Lui, W.Y., Liu, T.Y., Chi, C.W. Br. J. Cancer (2003) [Pubmed]
  33. Phosphoinositide 3-kinase-independent non-genomic signals transit from the androgen receptor to Akt1 in membrane raft microdomains. Cinar, B., Mukhopadhyay, N.K., Meng, G., Freeman, M.R. J. Biol. Chem. (2007) [Pubmed]
  34. Ca(2+)/calmodulin directly interacts with the pleckstrin homology domain of AKT1. Dong, B., Valencia, C.A., Liu, R. J. Biol. Chem. (2007) [Pubmed]
  35. Dissociation of Akt1 from its negative regulator JIP1 is mediated through the ASK1-MEK-JNK signal transduction pathway during metabolic oxidative stress: a negative feedback loop. Song, J.J., Lee, Y.J. J. Cell Biol. (2005) [Pubmed]
  36. Complex formation and cooperation of protein kinase C theta and Akt1/protein kinase B alpha in the NF-kappa B transactivation cascade in Jurkat T cells. Bauer, B., Krumböck, N., Fresser, F., Hochholdinger, F., Spitaler, M., Simm, A., Uberall, F., Schraven, B., Baier, G. J. Biol. Chem. (2001) [Pubmed]
  37. In vitro synergism between hybrid immunotoxins and chemotherapeutic drugs: relevance to immunotherapy of prostate carcinoma. Webb, K.S., Liberman, S.N., Ware, J.L., Walther, P.J. Cancer Immunol. Immunother. (1986) [Pubmed]
  38. PKB/Akt interacts with inosine-5' monophosphate dehydrogenase through its pleckstrin homology domain. Ingley, E., Hemmings, B.A. FEBS Lett. (2000) [Pubmed]
  39. Epidermal growth factor receptor, protein kinase B/Akt, and glioma response to erlotinib. Haas-Kogan, D.A., Prados, M.D., Tihan, T., Eberhard, D.A., Jelluma, N., Arvold, N.D., Baumber, R., Lamborn, K.R., Kapadia, A., Malec, M., Berger, M.S., Stokoe, D. J. Natl. Cancer Inst. (2005) [Pubmed]
  40. Mechanisms of endocrine therapy-responsive and -unresponsive prostate tumours. Culig, Z., Steiner, H., Bartsch, G., Hobisch, A. Endocr. Relat. Cancer (2005) [Pubmed]
  41. Two novel phosphorylation sites on FKHR that are critical for its nuclear exclusion. Rena, G., Woods, Y.L., Prescott, A.R., Peggie, M., Unterman, T.G., Williams, M.R., Cohen, P. EMBO J. (2002) [Pubmed]
  42. Inhibition of Chk1 by activated PKB/Akt. King, F.W., Skeen, J., Hay, N., Shtivelman, E. Cell Cycle (2004) [Pubmed]
  43. Functional role of death-associated protein 3 (DAP3) in anoikis. Miyazaki, T., Shen, M., Fujikura, D., Tosa, N., Kim, H.R., Kon, S., Uede, T., Reed, J.C. J. Biol. Chem. (2004) [Pubmed]
  44. The tumor suppressor PTEN positively regulates macroautophagy by inhibiting the phosphatidylinositol 3-kinase/protein kinase B pathway. Arico, S., Petiot, A., Bauvy, C., Dubbelhuis, P.F., Meijer, A.J., Codogno, P., Ogier-Denis, E. J. Biol. Chem. (2001) [Pubmed]
  45. Blockage of epidermal growth factor receptor-phosphatidylinositol 3-kinase-AKT signaling increases radiosensitivity of K-RAS mutated human tumor cells in vitro by affecting DNA repair. Toulany, M., Kasten-Pisula, U., Brammer, I., Wang, S., Chen, J., Dittmann, K., Baumann, M., Dikomey, E., Rodemann, H.P. Clin. Cancer Res. (2006) [Pubmed]
  46. Identification of a human Akt3 (protein kinase B gamma) which contains the regulatory serine phosphorylation site. Nakatani, K., Sakaue, H., Thompson, D.A., Weigel, R.J., Roth, R.A. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  47. Protein kinase B-alpha inhibits human pyruvate dehydrogenase kinase-4 gene induction by dexamethasone through inactivation of FOXO transcription factors. Kwon, H.S., Huang, B., Unterman, T.G., Harris, R.A. Diabetes (2004) [Pubmed]
  48. Akt/protein kinase B isoforms are differentially regulated by epidermal growth factor stimulation. Okano, J., Gaslightwala, I., Birnbaum, M.J., Rustgi, A.K., Nakagawa, H. J. Biol. Chem. (2000) [Pubmed]
  49. Cutaneous human papillomaviruses down-regulate AKT1, whereas AKT2 up-regulation and activation associates with tumors. O'Shaughnessy, R.F., Akgũl, B., Storey, A., Pfister, H., Harwood, C.A., Byrne, C. Cancer Res. (2007) [Pubmed]
  50. Human chorionic gonadotropin stimulates trophoblast invasion through extracellularly regulated kinase and AKT signaling. Prast, J., Saleh, L., Husslein, H., Sonderegger, S., Helmer, H., Knöfler, M. Endocrinology (2008) [Pubmed]
  51. A PDK1 homolog is necessary and sufficient to transduce AGE-1 PI3 kinase signals that regulate diapause in Caenorhabditis elegans. Paradis, S., Ailion, M., Toker, A., Thomas, J.H., Ruvkun, G. Genes Dev. (1999) [Pubmed]
  52. Inhibition of integrin-linked kinase (ILK) suppresses activation of protein kinase B/Akt and induces cell cycle arrest and apoptosis of PTEN-mutant prostate cancer cells. Persad, S., Attwell, S., Gray, V., Delcommenne, M., Troussard, A., Sanghera, J., Dedhar, S. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  53. Decreased phosphorylation of protein kinase B and extracellular signal-regulated kinase in neutrophils from patients with myelodysplasia. Fuhler, G.M., Drayer, A.L., Vellenga, E. Blood (2003) [Pubmed]
  54. Activation of p53-Dependent Growth Suppression in Human Cells by Mutations in PTEN or PIK3CA. Kim, J.S., Lee, C., Bonifant, C.L., Ressom, H., Waldman, T. Mol. Cell. Biol. (2007) [Pubmed]
  55. IRS-4 mediates protein kinase B signaling during insulin stimulation without promoting antiapoptosis. Uchida, T., Myers, M.G., White, M.F. Mol. Cell. Biol. (2000) [Pubmed]
  56. Increased AKT activity contributes to prostate cancer progression by dramatically accelerating prostate tumor growth and diminishing p27Kip1 expression. Graff, J.R., Konicek, B.W., McNulty, A.M., Wang, Z., Houck, K., Allen, S., Paul, J.D., Hbaiu, A., Goode, R.G., Sandusky, G.E., Vessella, R.L., Neubauer, B.L. J. Biol. Chem. (2000) [Pubmed]
  57. Increased phosphorylation of protein kinase B and related substrates after traumatic brain injury in humans and rats. Zhang, X., Chen, Y., Ikonomovic, M.D., Nathaniel, P.D., Kochanek, P.M., Marion, D.W., DeKosky, S.T., Jenkins, L.W., Clark, R.S. J. Cereb. Blood Flow Metab. (2006) [Pubmed]
  58. Photochemopreventive Effect of Pomegranate Fruit Extract on UVA-mediated Activation of Cellular Pathways in Normal Human Epidermal Keratinocytes. Syed, D.N., Malik, A., Hadi, N., Sarfaraz, S., Afaq, F., Mukhtar, H. Photochem. Photobiol. (2006) [Pubmed]
  59. Expression, purification, characterization and homology modeling of active Akt/PKB, a key enzyme involved in cell survival signaling. Kumar, C.C., Diao, R., Yin, Z., Liu, Y., Samatar, A.A., Madison, V., Xiao, L. Biochim. Biophys. Acta (2001) [Pubmed]
 
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