AKT1

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RAC-alpha serine/threonine-protein kinase is an enzyme that in humans is encoded by the AKT1 gene.


V-akt murine thymoma viral oncogene homolog 1

PDB rendering based on 1h10.
[show]Available structures
PDB 1h10, 1unp, 1unq, 1unr, 2uvm
 
Identifiers
Symbols AKT1; AKT; MGC99656; PKB; PRKBA; RAC; RAC-ALPHA
External IDs OMIM: 164730 MGI: 87986 HomoloGene: 3785 GeneCards: AKT1 Gene
[show]Gene Ontology
Molecular function • nucleotide binding
• protein kinase activity
• protein serine/threonine kinase activity
• sugar:hydrogen ion symporter activity
• ATP binding
• transferase activity
• identical protein binding
 
Cellular component • nucleus
• cytoplasm
• spindle
• lamellipodium
 
Biological process • protein import into nucleus, translocation
• carbohydrate metabolic process
• glycogen biosynthetic process
• glucose metabolic process
• regulation of translation
• protein amino acid phosphorylation
• nitric oxide biosynthetic process
• transport
• apoptosis
• inflammatory response
• signal transduction
• G-protein coupled receptor protein signaling pathway
• germ cell development
• insulin receptor signaling pathway
• apoptotic mitochondrial changes
• response to heat
• response to hormone stimulus
• glucose transport
• protein ubiquitination
• protein catabolic process
• anagen
• regulation of survival gene product activity
• protein amino acid autophosphorylation
• insulin-like growth factor receptor signaling pathway
 
Sources: Amigo / QuickGO
 
RNA expression pattern
 
More reference expression data
Orthologs
Species Human Mouse 
Entrez 207 11651 
Ensembl ENSG00000142208 ENSMUSG00000001729 
UniProt P31749 P31750 
RefSeq (mRNA) NM_001014431 NM_009652 
RefSeq (protein) NP_001014431 NP_033782 
Location (UCSC) Chr 14:
104.31 - 104.33 Mb Chr 12:
113.1 - 113.12 Mb 
PubMed search [1] [2] 

The serine-threonine protein kinase encoded by the AKT1 gene 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.

Multiple alternatively spliced transcript variants have been found for this gene.[1]

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 atk1 are also resistant to cancer: they experience considerable delay in tumor growth initiated by the large T antigen or the Neu oncogene.

HistoryAkt (now also called Akt1) was originally identified as the oncogene in the transforming retrovirus, AKT8.[2] 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.[3]

 Interactions

AKT1 has been shown to interact with Phosphoinositide-dependent kinase-1,[4][5] Keratin 10,[6] Integrin-linked kinase,[4][7][5] TSC2,[8][9] GAB2,[10] TRIB3,[11] NPM1,[12] BRCA1,[13][14] BRAF,[15] C-Raf,[16] MAPK14,[17] MARK2,[18] MAP2K4,[19] MTCP1,[20][21] TCL1A,[20][21][22] Nerve Growth factor IB,[23] MAPKAPK2,[17] PRKCQ,[24] Androgen receptor,[25] Heat shock protein 90kDa alpha (cytosolic), member A1,[26][27][28] Plexin A1,[29] MAP3K11,[30] TSC1,[9][8] MAP3K8,[31] Mammalian target of rapamycin,[32][33][34] PKN2,[35] AKTIP,[36] YWHAZ,[37] CHUK[38][39] and CDKN1B.[40]

References

1.^ "Entrez Gene: AKT1 v-akt murine thymoma viral oncogene homolog 1". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=207.
2.^ 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.
3.^ 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. http://www.pnas.org/content/84/14/5034.abstract.
4.^ 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.
5.^ 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.
6.^ Paramio, J M; Segrelles C, Ruiz S, Jorcano J L (Nov. 2001). "Inhibition of protein kinase B (PKB) and PKCzeta 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.
7.^ 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.
8.^ 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.
9.^ 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.
10.^ 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.
11.^ 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.
12.^ 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.
13.^ 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.
14.^ 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.
15.^ 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.
16.^ 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.
17.^ 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.
18.^ 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.
19.^ 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.
20.^ 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.
21.^ 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.
22.^ 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.
23.^ 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.
24.^ 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.
25.^ 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.
26.^ 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.
27.^ 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.
28.^ 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.
29.^ 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.
30.^ 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.
31.^ Kane, Lawrence P; Mollenauer Marianne N, Xu Zheng, Turck Christoph W, Weiss Arthur (Aug. 2002). "Akt-dependent phosphorylation specifically regulates Cot induction of NF-kappa B-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.
32.^ 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.
33.^ 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.
34.^ 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.
35.^ 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.
36.^ 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.
37.^ 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.
38.^ 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.
39.^ 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.
40.^ 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.
[edit] Further readingHemmings BA (1997). "Akt signaling: linking membrane events to life and death decisions.". Science 275 (5300): 628–30. doi:10.1126/science.275.5300.628. PMID 9019819.
Vanhaesebroeck B, Alessi DR (2000). "The PI3K-PDK1 connection: more than just a road to PKB.". Biochem. J. 346 Pt 3: 561–76. doi:10.1042/0264-6021:3460561. PMC 1220886. PMID 10698680. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1220886.
Chan TO, Rittenhouse SE, Tsichlis PN (2000). "AKT/PKB and other D3 phosphoinositide-regulated kinases: kinase activation by phosphoinositide-dependent phosphorylation.". Annu. Rev. Biochem. 68: 965–1014. doi:10.1146/annurev.biochem.68.1.965. PMID 10872470.
Pekarsky Y, Hallas C, Croce CM (2001). "Molecular basis of mature T-cell leukemia.". JAMA 286 (18): 2308–14. doi:10.1001/jama.286.18.2308. PMID 11710897.
Dickson LM, Rhodes CJ (2004). "Pancreatic beta-cell growth and survival in the onset of type 2 diabetes: a role for protein kinase B in the Akt?". Am. J. Physiol. Endocrinol. Metab. 287 (2): E192–8. doi:10.1152/ajpendo.00031.2004. PMID 15271644.
Manning BD (2004). "Balancing Akt with S6K: implications for both metabolic diseases and tumorigenesis.". J. Cell Biol. 167 (3): 399–403. doi:10.1083/jcb.200408161. PMC 2172491. PMID 15533996. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2172491.
Shinohara M, Chung YJ, Saji M, Ringel MD (2007). "AKT in thyroid tumorigenesis and progression.". Endocrinology 148 (3): 942–7. doi:10.1210/en.2006-0937. PMID 16946008.
[show]v · d · ePDB gallery
 
 
1h10: HIGH RESOLUTION STRUCTURE OF THE PLECKSTRIN HOMOLOGY DOMAIN OF PROTEIN KINASE B/AKT BOUND TO INS(1,3,4,5)-TETRAKISPHOPHATE  
 
1unp: CRYSTAL STRUCTURE OF THE PLECKSTRIN HOMOLOGY DOMAIN OF PKB ALPHA  
 
1unq: HIGH RESOLUTION CRYSTAL STRUCTURE OF THE PLECKSTRIN HOMOLOGY DOMAIN OF PROTEIN KINASE B/AKT BOUND TO INS (1,3,4,5)-TETRAKISPHOPHATE  
 
1unr: CRYSTAL STRUCTURE OF THE PH DOMAIN OF PKB ALPHA IN COMPLEX WITH A SULFATE MOLECULE  
 
2uvm: STRUCTURE OF PKBALPHA PH DOMAIN IN COMPLEX WITH A NOVEL INOSITOL HEADGROUP SURROGATE, BENZENE 1,2,3,4-TETRAKISPHOSPHATE  
 
 
 

[edit] See alsoAKT - 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
 

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