AKT1

From Wikipedia, the free encyclopedia
Jump to: navigation, search
V-akt murine thymoma viral oncogene homolog 1
PBB Protein AKT1 image.jpg
PDB rendering based on 1h10.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols AKT1 ; AKT; CWS6; PKB; PKB-ALPHA; PRKBA; RAC; RAC-ALPHA
External IDs OMIM164730 MGI87986 HomoloGene3785 ChEMBL: 4282 GeneCards: AKT1 Gene
EC number 2.7.11.1
RNA expression pattern
PBB GE AKT1 207163 s at fs.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 207 11651
Ensembl ENSG00000142208 ENSMUSG00000001729
UniProt P31749 P31750
RefSeq (mRNA) NM_001014431 NM_001165894
RefSeq (protein) NP_001014431 NP_001159366
Location (UCSC) Chr 14:
105.24 – 105.26 Mb
Chr 12:
112.65 – 112.67 Mb
PubMed search [1] [2]

RAC-alpha serine/threonine-protein kinase is an enzyme that in humans is encoded by the AKT1 gene. Multiple alternatively spliced transcript variants have been found for this gene.[1] It is commonly referred to as PKB, or by both names as "Akt/PKB".

Function[edit]

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]

History[edit]

Akt (now also called Akt1) was originally identified as the oncogene in the transforming retrovirus, AKT8.[3] 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.[4]

In 2011, a mutation in AKT1 was strongly associated with Proteus syndrome, the disease that probably affected the Elephant Man.[5]

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[edit]

AKT1 has been shown to interact with Phosphoinositide-dependent kinase-1,[6][7] Keratin 10,[8] Integrin-linked kinase,[6][7][9] TSC2,[10][11] GAB2,[12] TRIB3,[13] NPM1,[14] BRCA1,[15][16] BRAF,[17] C-Raf,[18] MAPK14,[19] MARK2,[20] MAP2K4,[21] MTCP1,[22][23] TCL1A,[22][23][24] Nerve Growth factor IB,[25] MAPKAPK2,[19] PRKCQ,[26] Androgen receptor,[27] Heat shock protein 90kDa alpha (cytosolic), member A1,[28][29][30] Plexin A1,[31] MAP3K11,[32] TSC1,[10][11] MAP3K8,[33] Mammalian target of rapamycin,[34][35][36] PKN2,[37] AKTIP,[38] YWHAZ,[39] CHUK[40][41] and CDKN1B.[42]

References[edit]

  1. ^ "Entrez Gene: AKT1 v-akt murine thymoma viral oncogene homolog 1". 
  2. ^ Lindhurst et al. A Mosaic Activating Mutation in AKT1 Associated with the Proteus Syndrome 28 July 2011
  3. ^ 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. 
  4. ^ 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. 
  5. ^ Lindhurst, Marjorie J.; Sapp, Julie C., Teer, Jamie K., Johnston, Jennifer J., Finn, Erin M., Peters, Kathryn, Turner, Joyce, Cannons, Jennifer L., Bick, David, Blakemore, Laurel, Blumhorst, Catherine, Brockmann, Knut, Calder, Peter, Cherman, Natasha, Deardorff, Matthew A., Everman, David B., Golas, Gretchen, Greenstein, Robert M., Kato, B. Maya, Keppler-Noreuil, Kim M., Kuznetsov, Sergei A., Miyamoto, Richard T., Newman, Kurt, Ng, David, O'Brien, Kevin, Rothenberg, Steven, Schwartzentruber, Douglas J., Singhal, Virender, Tirabosco, Roberto, Upton, Joseph, Wientroub, Shlomo, Zackai, Elaine H., Hoag, Kimberly, Whitewood-Neal, Tracey, Robey, Pamela G., Schwartzberg, Pamela L., Darling, Thomas N., Tosi, Laura L., Mullikin, James C., Biesecker, Leslie G. (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. 
  6. ^ a b Barry, Fiona A; Gibbins Jonathan M (Apr 2002). "Protein kinase B is regulated in platelets by the collagen receptor glycoprotein VI". J. Biol. Chem. (United States) 277 (15): 12874–8. doi:10.1074/jbc.M200482200. ISSN 0021-9258. PMID 11825911. 
  7. ^ a b Persad, S; Attwell S; Gray V; Mawji N; Deng J T; Leung D; Yan J; Sanghera J; Walsh M P; 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. (United States) 276 (29): 27462–9. doi:10.1074/jbc.M102940200. ISSN 0021-9258. PMID 11313365. 
  8. ^ Paramio, J M; Segrelles C; Ruiz S; Jorcano J L (Nov 2001). "Inhibition of Protein Kinase B (PKB) and PKCζ Mediates Keratin K10-Induced Cell Cycle Arrest". Mol. Cell. Biol. (United States) 21 (21): 7449–59. doi:10.1128/MCB.21.21.7449-7459.2001. ISSN 0270-7306. PMC 99917. PMID 11585925. 
  9. ^ 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. (UNITED STATES) 95 (19): 11211–6. doi:10.1073/pnas.95.19.11211. ISSN 0027-8424. PMC 21621. PMID 9736715. 
  10. ^ a b Dan, Han C; Sun Mei, Yang Lin, Feldman Richard I, Sui Xue-Mei, Ou Chien Chen, Nellist Mark, Yeung Raymond S, Halley Dicky J J, Nicosia Santo V, Pledger Warren J, Cheng Jin Q (Sep 2002). "Phosphatidylinositol 3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin". J. Biol. Chem. (United States) 277 (38): 35364–70. doi:10.1074/jbc.M205838200. ISSN 0021-9258. PMID 12167664. 
  11. ^ a b Roux, Philippe P; Ballif Bryan A; Anjum Rana; Gygi Steven P; Blenis John (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. (United States) 101 (37): 13489–94. doi:10.1073/pnas.0405659101. ISSN 0027-8424. PMC 518784. PMID 15342917. 
  12. ^ Lynch, Danielle K; Daly Roger J (Jan 2002). "PKB-mediated negative feedback tightly regulates mitogenic signalling via Gab2". EMBO J. (England) 21 (1–2): 72–82. doi:10.1093/emboj/21.1.72. ISSN 0261-4189. PMC 125816. PMID 11782427. 
  13. ^ Du, Keyong; Herzig Stephan; Kulkarni Rohit N; Montminy Marc (Jun 2003). "TRB3: a tribbles homolog that inhibits Akt/PKB activation by insulin in liver". Science (United States) 300 (5625): 1574–7. doi:10.1126/science.1079817. PMID 12791994. 
  14. ^ Lee, Sang Bae; Xuan Nguyen Truong L; Choi Joung Woo; Lee Kyung-Hoon; Cho Sung-Woo; Liu Zhixue; Ye Keqiang; Bae Sun Sik; Ahn Jee-Yin (Oct 2008). "Nuclear Akt interacts with B23/NPM and protects it from proteolytic cleavage, enhancing cell survival". Proc. Natl. Acad. Sci. U.S.A. (United States) 105 (43): 16584–9. doi:10.1073/pnas.0807668105. PMC 2569968. PMID 18931307. 
  15. ^ Altiok, S; Batt D; Altiok N; Papautsky A; Downward J; Roberts T M; Avraham H (Nov 1999). "Heregulin induces phosphorylation of BRCA1 through phosphatidylinositol 3-Kinase/AKT in breast cancer cells". J. Biol. Chem. (UNITED STATES) 274 (45): 32274–8. doi:10.1074/jbc.274.45.32274. ISSN 0021-9258. PMID 10542266. 
  16. ^ Xiang, Tao; Ohashi Amiko; Huang Yuping; Pandita Tej K; Ludwig Thomas; Powell Simon N; Yang Qin (Dec 2008). "Negative regulation of AKT activation by BRCA1". Cancer Res. (United States) 68 (24): 10040–4. doi:10.1158/0008-5472.CAN-08-3009. PMC 2605656. PMID 19074868. 
  17. ^ Guan, K L; Figueroa C; Brtva T R; Zhu T; Taylor J; Barber T D; Vojtek A B (Sep 2000). "Negative regulation of the serine/threonine kinase B-Raf by Akt". J. Biol. Chem. (UNITED STATES) 275 (35): 27354–9. doi:10.1074/jbc.M004371200. ISSN 0021-9258. PMID 10869359. 
  18. ^ Zimmermann, S; Moelling K (Nov 1999). "Phosphorylation and regulation of Raf by Akt (protein kinase B)". Science (UNITED STATES) 286 (5445): 1741–4. doi:10.1126/science.286.5445.1741. ISSN 0036-8075. PMID 10576742. 
  19. ^ a b Rane, M J; Coxon P Y; Powell D W; Webster R; Klein J B; Pierce W; Ping P; McLeish K R (Feb 2001). "p38 Kinase-dependent MAPKAPK-2 activation functions as 3-phosphoinositide-dependent kinase-2 for Akt in human neutrophils". J. Biol. Chem. (United States) 276 (5): 3517–23. doi:10.1074/jbc.M005953200. ISSN 0021-9258. PMID 11042204. 
  20. ^ Dickey, Chad A; Koren John, Zhang Yong-Jie, Xu Ya-Fei, Jinwal Umesh K, Birnbaum Morris J, Monks Bobby, Sun Mei, Cheng Jin Q, Patterson Cam, Bailey Rachel M, Dunmore Judith, Soresh Sareh, Leon Carlos, Morgan Dave, Petrucelli Leonard (Mar 2008). "Akt and CHIP coregulate tau degradation through coordinated interactions". Proc. Natl. Acad. Sci. U.S.A. (United States) 105 (9): 3622–7. doi:10.1073/pnas.0709180105. PMC 2265134. PMID 18292230. 
  21. ^ Park, Hee-Sae; Kim Mi-Sung; Huh Sung-Ho; Park Jihyun; Chung Jongkyeong; Kang Sang Sun; Choi Eui-Ju (Jan 2002). "Akt (protein kinase B) negatively regulates SEK1 by means of protein phosphorylation". J. Biol. Chem. (United States) 277 (4): 2573–8. doi:10.1074/jbc.M110299200. ISSN 0021-9258. PMID 11707464. 
  22. ^ a b Laine, Jarmo; Künstle Gerald; Obata Toshiyuki; Noguchi Masayuki (Feb 2002). "Differential regulation of Akt kinase isoforms by the members of the TCL1 oncogene family". J. Biol. Chem. (United States) 277 (5): 3743–51. doi:10.1074/jbc.M107069200. ISSN 0021-9258. PMID 11707444. 
  23. ^ a b Laine, J; Künstle G; Obata T; Sha M; Noguchi M (Aug 2000). "The protooncogene TCL1 is an Akt kinase coactivator". Mol. Cell (UNITED STATES) 6 (2): 395–407. doi:10.1016/S1097-2765(00)00039-3. ISSN 1097-2765. PMID 10983986. 
  24. ^ French, Samuel W; Shen Rhine R; Koh Patricia J; Malone Cindy S; Mallick Parag; Teitell Michael A (May 2002). "A modeled hydrophobic domain on the TCL1 oncoprotein mediates association with AKT at the cytoplasmic membrane". Biochemistry (United States) 41 (20): 6376–82. doi:10.1021/bi016068o. ISSN 0006-2960. PMID 12009899. 
  25. ^ Pekarsky, Y; Hallas C; Palamarchuk A; Koval A; Bullrich F; Hirata Y; Bichi R; Letofsky J; Croce C M (Mar 2001). "Akt phosphorylates and regulates the orphan nuclear receptor Nur77". Proc. Natl. Acad. Sci. U.S.A. (United States) 98 (7): 3690–4. doi:10.1073/pnas.051003198. ISSN 0027-8424. PMC 31113. PMID 11274386. 
  26. ^ 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. (United States) 276 (34): 31627–34. doi:10.1074/jbc.M103098200. ISSN 0021-9258. PMID 11410591. 
  27. ^ Lin, H K; Yeh S; Kang H Y; Chang C (Jun 2001). "Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor". Proc. Natl. Acad. Sci. U.S.A. (United States) 98 (13): 7200–5. doi:10.1073/pnas.121173298. ISSN 0027-8424. PMC 34646. PMID 11404460. 
  28. ^ Haendeler, Judith; Hoffmann Jörg; Rahman Sandy; Zeiher Andreas M; Dimmeler Stefanie (Feb 2003). "Regulation of telomerase activity and anti-apoptotic function by protein-protein interaction and phosphorylation". FEBS Lett. (Netherlands) 536 (1–3): 180–6. doi:10.1016/S0014-5793(03)00058-9. ISSN 0014-5793. PMID 12586360. 
  29. ^ Kawauchi, Kiyotaka; Ihjima Kimiko; Yamada Osamu (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. (United States) 174 (9): 5261–9. ISSN 0022-1767. PMID 15843522. 
  30. ^ Sato, S; Fujita N; Tsuruo T (Sep 2000). "Modulation of Akt kinase activity by binding to Hsp90". Proc. Natl. Acad. Sci. U.S.A. (UNITED STATES) 97 (20): 10832–7. doi:10.1073/pnas.170276797. ISSN 0027-8424. PMC 27109. PMID 10995457. 
  31. ^ Turner, Laura J; Nicholls Sarah; Hall Alan (Aug 2004). "The activity of the plexin-A1 receptor is regulated by Rac". J. Biol. Chem. (United States) 279 (32): 33199–205. doi:10.1074/jbc.M402943200. ISSN 0021-9258. PMID 15187088. 
  32. ^ Barthwal, Manoj K; Sathyanarayana Pradeep; Kundu Chanakya N; Rana Basabi; Pradeep Anamika; Sharma Chandan; Woodgett James R; Rana Ajay (Feb 2003). "Negative regulation of mixed lineage kinase 3 by protein kinase B/AKT leads to cell survival". J. Biol. Chem. (United States) 278 (6): 3897–902. doi:10.1074/jbc.M211598200. ISSN 0021-9258. PMID 12458207. 
  33. ^ Kane, Lawrence P; Mollenauer Marianne N; Xu Zheng; Turck Christoph W; Weiss Arthur (Aug 2002). "Akt-Dependent Phosphorylation Specifically Regulates Cot Induction of NF-κB-Dependent Transcription". Mol. Cell. Biol. (United States) 22 (16): 5962–74. doi:10.1128/MCB.22.16.5962-5974.2002. ISSN 0270-7306. PMC 133991. PMID 12138205. 
  34. ^ Sarbassov, D D; Guertin David A; Ali Siraj M; Sabatini David M (Feb 2005). "Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex". Science (United States) 307 (5712): 1098–101. doi:10.1126/science.1106148. PMID 15718470. 
  35. ^ Sekulić, A; Hudson C C; Homme J L; Yin P; Otterness D M; Karnitz L M; Abraham R T (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. (UNITED STATES) 60 (13): 3504–13. ISSN 0008-5472. PMID 10910062. 
  36. ^ Cheng, Susan W Y; Fryer Lee G D; Carling David; Shepherd Peter R (Apr 2004). "Thr2446 is a novel mammalian target of rapamycin (mTOR) phosphorylation site regulated by nutrient status". J. Biol. Chem. (United States) 279 (16): 15719–22. doi:10.1074/jbc.C300534200. ISSN 0021-9258. PMID 14970221. 
  37. ^ Koh, H; Lee K H; Kim D; Kim S; Kim J W; 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. (UNITED STATES) 275 (44): 34451–8. doi:10.1074/jbc.M001753200. ISSN 0021-9258. PMID 10926925. 
  38. ^ Remy, Ingrid; Michnick Stephen W (Feb 2004). "Regulation of Apoptosis by the Ft1 Protein, a New Modulator of Protein Kinase B/Akt". Mol. Cell. Biol. (United States) 24 (4): 1493–504. doi:10.1128/MCB.24.4.1493-1504.2004. ISSN 0270-7306. PMC 344167. PMID 14749367. 
  39. ^ Powell, David W; Rane Madhavi J; Chen Qingdan; Singh Saurabh; McLeish Kenneth R (Jun 2002). "Identification of 14-3-3zeta as a protein kinase B/Akt substrate". J. Biol. Chem. (United States) 277 (24): 21639–42. doi:10.1074/jbc.M203167200. ISSN 0021-9258. PMID 11956222. 
  40. ^ Ozes, O N; Mayo L D; Gustin J A; Pfeffer S R; Pfeffer L M; Donner D B (Sep 1999). "NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase". Nature (ENGLAND) 401 (6748): 82–5. doi:10.1038/43466. ISSN 0028-0836. PMID 10485710. 
  41. ^ Romashkova, J A; Makarov S S (Sep 1999). "NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling". Nature (ENGLAND) 401 (6748): 86–90. doi:10.1038/43474. ISSN 0028-0836. PMID 10485711. 
  42. ^ Fujita, Naoya; Sato Saori; Katayama Kazuhiro; Tsuruo Takashi (Aug 2002). "Akt-dependent phosphorylation of p27Kip1 promotes binding to 14-3-3 and cytoplasmic localization". J. Biol. Chem. (United States) 277 (32): 28706–13. doi:10.1074/jbc.M203668200. ISSN 0021-9258. PMID 12042314. 

Further reading[edit]

See also[edit]

  • 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