AKT1

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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RAC-alpha serine/threonine-protein kinase is an enzyme that in humans is encoded by the AKT1 gene. This enzyme belongs to the AKT subfamily of serine/threonine kinases that contain SH2 (Src homology 2-like) domains.[1] It is commonly referred to as PKB, or by both names as "Akt/PKB".

Function

The serine-threonine protein kinase AKT1 is catalytically inactive in serum-starved primary and immortalized fibroblasts. AKT1 and the related AKT2 are activated by platelet-derived growth factor. The activation is rapid and specific, and it is abrogated by mutations in the pleckstrin homology domain of AKT1. It was shown that the activation occurs through phosphatidylinositol 3-kinase. In the developing nervous system AKT is a critical mediator of growth factor-induced neuronal survival. Survival factors can suppress apoptosis in a transcription-independent manner by activating the serine/threonine kinase AKT1, which then phosphorylates and inactivates components of the apoptotic machinery. Mice lacking Akt1 display a 25% reduction in body mass, indicating that Akt1 is critical for transmitting growth-promoting signals, most likely via the IGF1 receptor. Mice lacking Akt1 are also resistant to cancer: They experience considerable delay in tumor growth initiated by the large T antigen or the Neu oncogene. A single-nucleotide polymorphism in this gene causes Proteus syndrome.[2][3]

History

AKT (now also called AKT1) was originally identified as the oncogene in the transforming retrovirus, AKT8.[4] AKT8 was isolated from a spontaneous thymoma cell line derived from AKR mice 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.[5]

In 2011, a mutation in AKT1 was strongly associated with Proteus syndrome, the disease that probably affected the Elephant Man.[6]

The name Akt stands for Ak strain transforming. The origins of the Akt name date back to 1928, where J. Furth performed experimental studies on mice that developed spontaneous thymic lymphomas. Mice from three different stocks were studied, and the stocks were designated A, R, and S. Stock A was noted to yield many cancers, and inbred families were subsequently designated by a second small letter (Aa, Ab, Ac, etc.), and thus came the Ak strain of mice. Further inbreeding was undertaken with Ak mice at the Rockefeller Institute in 1936, leading to the designation of the AKR mouse strain. In 1977, a transforming retrovirus was isolated from the AKR mouse. This virus was named Akt-8, the "t" representing its transforming capabilities.

Interactions

AKT1 has been shown to interact with:

See also

  • AKT – the AKT family of proteins
  • AKT2 – the gene for the second member of the AKT family
  • AKT3 – the gene for the third member of the AKT family
  • Proteus syndrome

References

  1. ↑ "Entrez Gene: AKT1 v-akt murine thymoma viral oncogene homolog 1".
  2. ↑ Lindhurst MJ, Sapp JC, Teer JK, Johnston JJ, Finn EM, Peters K, Turner J, Cannons JL, Bick D, Blakemore L, Blumhorst C, Brockmann K, Calder P, Cherman N, Deardorff MA, Everman DB, Golas G, Greenstein RM, Kato BM, Keppler-Noreuil KM, Kuznetsov SA, Miyamoto RT, Newman K, Ng D, O'Brien K, Rothenberg S, Schwartzentruber DJ, Singhal V, Tirabosco R, Upton J, Wientroub S, Zackai EH, Hoag K, Whitewood-Neal T, Robey PG, Schwartzberg PL, Darling TN, Tosi LL, Mullikin JC, Biesecker LG (2011). "A mosaic activating mutation in AKT1 associated with the Proteus syndrome". N. Engl. J. Med. 365 (7): 611–9. doi:10.1056/NEJMoa1104017. PMC 3170413. PMID 21793738.
  3. ↑ Cohen MM (2014). "Proteus syndrome review: molecular, clinical, and pathologic features". Clin. Genet. 85 (2): 111–9. doi:10.1111/cge.12266. PMID 23992099.
  4. ↑ 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. doi:10.1073/pnas.74.7.3065. PMC 431413. PMID 197531.
  5. ↑ 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. doi:10.1073/pnas.84.14.5034. PMC 305241. PMID 3037531.
  6. ↑ Lindhurst MJ, Sapp JC, Teer JK, Johnston JJ, Finn EM, Peters K, Turner J, Cannons JL, Bick D, Blakemore L, Blumhorst C, Brockmann K, Calder P, Cherman N, Deardorff MA, Everman DB, Golas G, Greenstein RM, Kato BM, Keppler-Noreuil KM, Kuznetsov SA, Miyamoto RT, Newman K, Ng D, O'Brien K, Rothenberg S, Schwartzentruber DJ, Singhal V, Tirabosco R, Upton J, Wientroub S, Zackai EH, Hoag K, Whitewood-Neal T, Robey PG, Schwartzberg PL, Darling TN, Tosi LL, Mullikin JC, Biesecker LG (27 July 2011). "A Mosaic Activating Mutation in Associated with the Proteus Syndrome". New England Journal of Medicine. 365 (7): 110727140030013. doi:10.1056/NEJMoa1104017. PMC 3170413. PMID 21793738.
  7. ↑ Remy I, Michnick SW (Feb 2004). "Regulation of apoptosis by the Ft1 protein, a new modulator of protein kinase B/Akt". Mol. Cell. Biol. 24 (4): 1493–504. doi:10.1128/mcb.24.4.1493-1504.2004. PMC 344167. PMID 14749367.
  8. ↑ Guan KL, Figueroa C, Brtva TR, Zhu T, Taylor J, Barber TD, Vojtek AB (Sep 2000). "Negative regulation of the serine/threonine kinase B-Raf by Akt". J. Biol. Chem. 275 (35): 27354–9. doi:10.1074/jbc.M004371200. PMID 10869359.
  9. ↑ Altiok S, Batt D, Altiok N, Papautsky A, Downward J, Roberts TM, Avraham H (Nov 1999). "Heregulin induces phosphorylation of BRCA1 through phosphatidylinositol 3-Kinase/AKT in breast cancer cells". J. Biol. Chem. 274 (45): 32274–8. doi:10.1074/jbc.274.45.32274. PMID 10542266.
  10. ↑ Xiang T, Ohashi A, Huang Y, Pandita TK, Ludwig T, Powell SN, Yang Q (Dec 2008). "Negative Regulation of AKT Activation by BRCA1". Cancer Res. 68 (24): 10040–4. doi:10.1158/0008-5472.CAN-08-3009. PMC 2605656. PMID 19074868.
  11. ↑ Zimmermann S, Moelling K (Nov 1999). "Phosphorylation and regulation of Raf by Akt (protein kinase B)". Science. 286 (5445): 1741–4. doi:10.1126/science.286.5445.1741. PMID 10576742.
  12. ↑ Fujita N, Sato S, Katayama K, Tsuruo T (Aug 2002). "Akt-dependent phosphorylation of p27Kip1 promotes binding to 14-3-3 and cytoplasmic localization". J. Biol. Chem. 277 (32): 28706–13. doi:10.1074/jbc.M203668200. PMID 12042314.
  13. ↑ Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB (Sep 1999). "NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase". Nature. 401 (6748): 82–5. doi:10.1038/43466. PMID 10485710.
  14. ↑ Romashkova JA, Makarov SS (Sep 1999). "NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling". Nature. 401 (6748): 86–90. doi:10.1038/43474. PMID 10485711.
  15. ↑ Lynch DK, Daly RJ (Jan 2002). "PKB-mediated negative feedback tightly regulates mitogenic signalling via Gab2". EMBO J. 21 (1–2): 72–82. doi:10.1093/emboj/21.1.72. PMC 125816. PMID 11782427.
  16. ↑ Haendeler J, Hoffmann J, Rahman S, Zeiher AM, Dimmeler S (Feb 2003). "Regulation of telomerase activity and anti-apoptotic function by protein-protein interaction and phosphorylation". FEBS Lett. 536 (1–3): 180–6. doi:10.1016/s0014-5793(03)00058-9. PMID 12586360.
  17. ↑ Kawauchi K, Ihjima K, Yamada O (May 2005). "IL-2 increases human telomerase reverse transcriptase activity transcriptionally and posttranslationally through phosphatidylinositol 3'-kinase/Akt, heat shock protein 90, and mammalian target of rapamycin in transformed NK cells". J. Immunol. 174 (9): 5261–9. doi:10.4049/jimmunol.174.9.5261. PMID 15843522.
  18. ↑ Sato S, Fujita N, Tsuruo T (Sep 2000). "Modulation of Akt kinase activity by binding to Hsp90". Proc. Natl. Acad. Sci. U.S.A. 97 (20): 10832–7. doi:10.1073/pnas.170276797. PMC 27109. PMID 10995457.
  19. ↑ 19.0 19.1 Barry FA, Gibbins JM (Apr 2002). "Protein kinase B is regulated in platelets by the collagen receptor glycoprotein VI". J. Biol. Chem. 277 (15): 12874–8. doi:10.1074/jbc.M200482200. PMID 11825911.
  20. ↑ 20.0 20.1 Persad S, Attwell S, Gray V, Mawji N, Deng JT, Leung D, Yan J, Sanghera J, Walsh MP, Dedhar S (Jul 2001). "Regulation of protein kinase B/Akt-serine 473 phosphorylation by integrin-linked kinase: critical roles for kinase activity and amino acids arginine 211 and serine 343". J. Biol. Chem. 276 (29): 27462–9. doi:10.1074/jbc.M102940200. PMID 11313365.
  21. ↑ Delcommenne M, Tan C, Gray V, Rue L, Woodgett J, Dedhar S (Sep 1998). "Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase". Proc. Natl. Acad. Sci. U.S.A. 95 (19): 11211–6. doi:10.1073/pnas.95.19.11211. PMC 21621. PMID 9736715.
  22. ↑ Paramio JM, Segrelles C, Ruiz S, Jorcano JL (Nov 2001). "Inhibition of protein kinase B (PKB) and PKCzeta mediates keratin K10-induced cell cycle arrest". Mol. Cell. Biol. 21 (21): 7449–59. doi:10.1128/MCB.21.21.7449-7459.2001. PMC 99917. PMID 11585925.
  23. ↑ Park HS, Kim MS, Huh SH, Park J, Chung J, Kang SS, Choi EJ (Jan 2002). "Akt (protein kinase B) negatively regulates SEK1 by means of protein phosphorylation". J. Biol. Chem. 277 (4): 2573–8. doi:10.1074/jbc.M110299200. PMID 11707464.
  24. ↑ Barthwal MK, Sathyanarayana P, Kundu CN, Rana B, Pradeep A, Sharma C, Woodgett JR, Rana A (Feb 2003). "Negative regulation of mixed lineage kinase 3 by protein kinase B/AKT leads to cell survival". J. Biol. Chem. 278 (6): 3897–902. doi:10.1074/jbc.M211598200. PMID 12458207.
  25. ↑ Kane LP, Mollenauer MN, Xu Z, Turck CW, Weiss A (Aug 2002). "Akt-dependent phosphorylation specifically regulates Cot induction of NF-kappa B-dependent transcription". Mol. Cell. Biol. 22 (16): 5962–74. doi:10.1128/mcb.22.16.5962-5974.2002. PMC 133991. PMID 12138205.
  26. ↑ 26.0 26.1 Rane MJ, Coxon PY, Powell DW, Webster R, Klein JB, Pierce W, Ping P, McLeish KR (Feb 2001). "p38 Kinase-dependent MAPKAPK-2 activation functions as 3-phosphoinositide-dependent kinase-2 for Akt in human neutrophils". J. Biol. Chem. 276 (5): 3517–23. doi:10.1074/jbc.M005953200. PMID 11042204.
  27. ↑ Dickey CA, Koren J, Zhang YJ, Xu YF, Jinwal UK, Birnbaum MJ, Monks B, Sun M, Cheng JQ, Patterson C, Bailey RM, Dunmore J, Soresh S, Leon C, Morgan D, Petrucelli L (Mar 2008). "Akt and CHIP coregulate tau degradation through coordinated interactions". Proc. Natl. Acad. Sci. U.S.A. 105 (9): 3622–7. doi:10.1073/pnas.0709180105. PMC 2265134. PMID 18292230.
  28. ↑ 28.0 28.1 Laine J, Künstle G, Obata T, Noguchi M (Feb 2002). "Differential regulation of Akt kinase isoforms by the members of the TCL1 oncogene family". J. Biol. Chem. 277 (5): 3743–51. doi:10.1074/jbc.M107069200. PMID 11707444.
  29. ↑ 29.0 29.1 Laine J, Künstle G, Obata T, Sha M, Noguchi M (Aug 2000). "The protooncogene TCL1 is an Akt kinase coactivator". Mol. Cell. 6 (2): 395–407. doi:10.1016/S1097-2765(00)00039-3. PMID 10983986.
  30. ↑ Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (Feb 2005). "Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex". Science. 307 (5712): 1098–101. doi:10.1126/science.1106148. PMID 15718470.
  31. ↑ Sekulić A, Hudson CC, Homme JL, Yin P, Otterness DM, Karnitz LM, Abraham RT (Jul 2000). "A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells". Cancer Res. 60 (13): 3504–13. PMID 10910062.
  32. ↑ Cheng SW, Fryer LG, Carling D, Shepherd PR (Apr 2004). "Thr2446 is a novel mammalian target of rapamycin (mTOR) phosphorylation site regulated by nutrient status". J. Biol. Chem. 279 (16): 15719–22. doi:10.1074/jbc.C300534200. PMID 14970221.
  33. ↑ Lee SB, Xuan Nguyen TL, Choi JW, Lee KH, Cho SW, Liu Z, Ye K, Bae SS, Ahn JY (Oct 2008). "Nuclear Akt interacts with B23/NPM and protects it from proteolytic cleavage, enhancing cell survival". Proc. Natl. Acad. Sci. U.S.A. 105 (43): 16584–9. doi:10.1073/pnas.0807668105. PMC 2569968. PMID 18931307.
  34. ↑ Pekarsky Y, Hallas C, Palamarchuk A, Koval A, Bullrich F, Hirata Y, Bichi R, Letofsky J, Croce CM (Mar 2001). "Akt phosphorylates and regulates the orphan nuclear receptor Nur77". Proc. Natl. Acad. Sci. U.S.A. 98 (7): 3690–4. doi:10.1073/pnas.051003198. PMC 31113. PMID 11274386.
  35. ↑ Lin HK, Yeh S, Kang HY, Chang C (Jun 2001). "Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor". Proc. Natl. Acad. Sci. U.S.A. 98 (13): 7200–5. doi:10.1073/pnas.121173298. PMC 34646. PMID 11404460.
  36. ↑ Koh H, Lee KH, Kim D, Kim S, Kim JW, Chung J (Nov 2000). "Inhibition of Akt and its anti-apoptotic activities by tumor necrosis factor-induced protein kinase C-related kinase 2 (PRK2) cleavage". J. Biol. Chem. 275 (44): 34451–8. doi:10.1074/jbc.M001753200. PMID 10926925.
  37. ↑ Bauer B, Krumböck N, Fresser F, Hochholdinger F, Spitaler M, Simm A, Uberall F, Schraven B, Baier G (Aug 2001). "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". J. Biol. Chem. 276 (34): 31627–34. doi:10.1074/jbc.M103098200. PMID 11410591.
  38. ↑ Turner LJ, Nicholls S, Hall A (Aug 2004). "The activity of the plexin-A1 receptor is regulated by Rac". J. Biol. Chem. 279 (32): 33199–205. doi:10.1074/jbc.M402943200. PMID 15187088.
  39. ↑ French SW, Shen RR, Koh PJ, Malone CS, Mallick P, Teitell MA (May 2002). "A modeled hydrophobic domain on the TCL1 oncoprotein mediates association with AKT at the cytoplasmic membrane". Biochemistry. 41 (20): 6376–82. doi:10.1021/bi016068o. PMID 12009899.
  40. ↑ Du K, Herzig S, Kulkarni RN, Montminy M (Jun 2003). "TRB3: a tribbles homolog that inhibits Akt/PKB activation by insulin in liver". Science. 300 (5625): 1574–7. doi:10.1126/science.1079817. PMID 12791994.
  41. ↑ 41.0 41.1 Dan HC, Sun M, Yang L, Feldman RI, Sui XM, Ou CC, Nellist M, Yeung RS, Halley DJ, Nicosia SV, Pledger WJ, Cheng JQ (Sep 2002). "Phosphatidylinositol 3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin". J. Biol. Chem. 277 (38): 35364–70. doi:10.1074/jbc.M205838200. PMID 12167664.
  42. ↑ 42.0 42.1 Roux PP, Ballif BA, Anjum R, Gygi SP, Blenis J (Sep 2004). "Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase". Proc. Natl. Acad. Sci. U.S.A. 101 (37): 13489–94. doi:10.1073/pnas.0405659101. PMC 518784. PMID 15342917.
  43. ↑ Powell DW, Rane MJ, Chen Q, Singh S, McLeish KR (Jun 2002). "Identification of 14-3-3zeta as a protein kinase B/Akt substrate". J. Biol. Chem. 277 (24): 21639–42. doi:10.1074/jbc.M203167200. PMID 11956222.

Further reading

External links

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