Atlas of Genetics and Cytogenetics in Oncology and Haematology


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AKT1 (v-akt murine thymoma viral oncogene homolog 1)

Identity

Other namesAKT
C-AKT
EC 2.7.11.1
MGC99656
PKB
PKB-ALPHA
PRKBA
RAC
RAC-ALPHA
RAC-PK-alpha
HGNC (Hugo) AKT1
LocusID (NCBI) 207
Location 14q32.33
Location_base_pair Starts at 105235687 and ends at 105262080 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Note Location in the mouse: chromosome 12, 57.0 cM, 113892032 to 113912401 bp, complement strand.
For a comparison of the gene location among Homo sapiens, mouse and rat see: NCBI Map Viewer.

DNA/RNA

 
  a. Genomic organization of human AKT1. The line indicates untranslated regions and boxes indicate coding regions (exon 1-14) of the gene. Exon and intron lengths (in bp) are reported in the upper and lower part of the diagram, respectively. The ATG transcription start site is located in exon 2 and the TGA termination codon is located in exon 14.
b. mRNA of human AKT1.
Description The human AKT1 gene is composed of 14 exons spanning a genomic region of about 26.4 Kb. The open reading frame of the coding region is 1443 bp.
Transcription The human AKT1 coding sequence consists of 1443 bp from the start codon to the stop codon. Multiple alternatively spliced transcript variants have been found for this gene (Entrez Gene).
Pseudogene No pseudogene of AKT1 known.

Protein

Note Although the AKT isoforms are activated in a similar manner and share the same downstream substrates, indicating functional redundancy of the AKT isoforms, their biological function is likely to be different in AKT-knockout mouse models. AKT1 mutant mice display developmental defects, showing decreased size in all organs and impaired placental development (Yang et al., 2004). AKT1 deficient mice exhibit perinatal morbidity with partial lethality between E13.5 and 3 weeks after birth and growth retardation. Surviving adults are fertile, but show 20% weight reduction accompanied by reduced sizes of multiple organs, and enhanced apoptosis in some cell types. No effect seen on glucose metabolism. Moreover, AKT1/AKT2 double-knockout mice display impeded adipogenesis, severe growth deficiency including impaired skin development, severe muscle atrophy, impaired bone development and die shortly after birth (Peng et al., 2003).
 
  a. Diagram of the human AKT1 protein in scale. The protein domains and their length (indicated by number of limiting residues) are reported. AKT1 contains a pleckstrin homology domain (PH), an helical region (Helix), a kinase domain (Kinase), and a regulatory motif (Regulatory). The two phosphorylation sites essential for complete activation of AKT1 (threonine 308, serine 473) are indicated in the diagram. C: carboxyl-terminal; N: amino-terminal.
b. Schematic representation of the AKT signaling activation and regulation.
Description Structure. AKT1 protein consists of 480 amino acids, with a molecular weight of 55,686 Da. AKT1 is constituted by a PH domain, a short helical region, a catalytic kinase domain and a regulatory hydrophobic motif.
PH domain is a conserved domain of about 100 residues that occurs in a wide range of proteins involved as cytoskeletal constituents or in intracellular signaling; the structure of the PH domain consists of two perpendicular anti-parallel beta-sheets followed by a C-terminal amphipathic helix; the common fold of PH domains is electrostatically polarized. The PH domain recruits AKT to the plasma membrane by phosphoinositides binding and is required for activation.
The kinase domain has been evolutionarily conserved from Escherichia coli to Homo sapiens; conserved regions are: i) a glycine-rich stretch of residues in close proximity of a lysine amino acid (179, by similarity), involved in ATP binding; ii) an highly conserved activation loop, called T-loop, located between DFG and APE motifs, with a threonine residue important for enzyme activation; iii) a conserved aspartic acid (274, by similarity) as proton acceptor residue, important for the catalytic activity of the enzyme. The kinase domain catalyzes the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on a consensus sequence on protein substrates, resulting in a conformational change affecting protein function, cellular location or association with other proteins (Knighton et al., 1991).
The carboxyl-terminal hydrophobic regulatory domain contains several proline-rich regions that potentially serve as protein-protein interaction sites with important roles in regulation of AKT1 activity; this region contains the 473 residue important for the activation process. This domain possesses the F-X-X-F/Y-S/T-Y/F hydrophobic motif, where X is any amino acid, that is characteristic of the AGC kinase family; in mammalian AKT isoforms, this motif is identical (FPQFSY) and is thought to be very important for the enzymatic activity. The conserved SH3-domain binding motif P-X-X-P in the regulatory region is involved in the interaction between AKT1 and its upstream tyrosine kinase Src (Jiang et al., 2003).
The crystallographic structure of AKT1 has been solved (PDB ID 3CQW, 3CQU).

Activation. The serine-threonine protein kinase AKT1 is a catalytically inactive cytoplasmic protein. AKT activation occurs by means of stimulation of the growth factor receptor-associated phosphatidylinositol 3-kinase (PI3K) and is a multi-step process that involves both membrane translocation and phosphorylation. When PI3K is activated by either growth factors, cytokines or hormones, PI3K generates 3'-phosphorylated phosphoinositides, i.e. phosphatidylinositol-3,4,5-trisphosphate (PIP3) and phosphatidylinositol-3,4-bisphosphate (PIP2) at the plasma membrane. Both phospholipids bind with high affinity to the PH domain, mediating membrane translocation of AKT. At the membrane, AKT1 is phosphorylated at threonine 308 by PDK1 (Andjelkovic et al., 1997; Walker et al., 1998) and at serine 473 by a second kinase identified with mTOR when bound to Rictor in the so called TORC2 complex (Santos et al., 2001; Sarbassov et al., 2005); however, it is still controversial if this second phosphorylation may occur by DNA-dependent protein kinase (Feng et al., 2004; Hill et al., 2002). Other kinases that have been reported to phosphorylate serine 473 are PKC (Kawakami et al., 2004), integrin-linked kinase (ILK) (Troussard et al., 2003; Lynch et al., 1999; Delcommenne et al., 1998), MAP kinase-activated protein kinase-2 (MK2) (Rane et al., 2001), PDK-1 (Balendran et al., 1999) or Akt itself (Toker et al., 2000). The full activation of AKT1 requires phosphorylation at both sites; threonine 308 phosphorylation increases the enzymatic activity up to 100-fold and serine 473 phosphorylation by a further 10-fold, thus both phosphorylation events enhance AKT1 activity by 1000-fold (Kumar et al., 2005; Alessi et al., 1996). The activation is rapid and specific, and it is abrogated by mutations in the AKT PH domain. Once activated, AKT1 dissociates from the membrane and phosphorylates targets in the cytoplasm and the cell nucleus.
Beside these essential activation sites, threonine 72 and serine 246 residues undergo auto-phosphorylation (Li et al., 2006), serine 124 and threonine 450 residues are constitutively phosphorylated, while tyrosine 315 and 326 in the activation loop can be phosphorylated by Src kinase, maybe regulating AKT1 activity (Chen et al., 2001).

Regulation. AKT activation is inversely regulated by phosphatases: PH domain leucine-rich repeat protein phosphatase (PHLPP) dephosphorylates the serine 473 residue of AKT1 (Brognard et al., 2007), and protein phosphatase 2 (PP2) dephosphorylates the threonine 308 residue (Gao et al., 2005). PI(3,4,5)P3 is hydrolyzed by phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and Src homology domain-containing inositol phosphatases SHIP1/SHIP2. PTEN antagonizes PI3K activity by removing the phosphate at the D3 position generating PI(4,5)P2 (Maehama et al., 1998), while SHIP1/2 dephosphorylates the D5 position to produce PI(3,4)P2 (Deleris et al., 2003; Damen et al., 1996).

Expression AKT1 is the predominant isoform in the major part of tissues as determined by using quantitative RT-PCR (Yang et al., 2003) and is ubiquitously expressed in most tissues at high levels and in all the human cell types so far analyzed (Hanada et al., 2004; Zinda et al., 2001). A Northern blot analysis of AKT1 in rat tissues indicated lower expression levels in kidney, liver, and spleen (Coffer et al., 1991).
Localisation AKT1 protein is predominantly cytoplasmic; it has been found at the plasma membrane for its activation and activated AKT1 is able to translocate into the nucleus. AKT1 translocation into nucleus has been demonstrated in several cell lines in response to stimuli as after IGF-I treatment of NIH3T3 cells (Meier, 1997), NGF stimulation of PC12 cells (Xuan Nguyen et al., 2006; Borgatti et al., 2003), EPO in K562 cells and IGF-I or PDGF mitogen factors in MC3T3 (Neri et al., 2002). Also if AKT1 contains a sequence for nuclear export rich in leucine (Saji et al., 2005) and some proteins may have a role of localization signal for its intranuclear migration, a nuclear localisation sequence on AKT1 inside motif has not yet been identified.
Function AKT mediates many of the downstream events of the PI3K signal transduction pathway by its serine-threonine kinase activity. AKT exhibits tight control over cell viability and proliferation, having main role in apoptosis inhibition and promotion of cell cycle progression. AKT is involved also in differentiation; in nervous system development AKT is a critical mediator of growth factor-induced neuronal survival. Further, AKT mediates glucose metabolism, angiogenesis, translation, transcriptional events, pre-mRNA splicing and other important nuclear functions such as chromatin condensation and genes transactivation.
AKT exerts its kinase activity toward proteins containing the minimal consensus sequence R/K-X-R/K-X-X-S/T, where S or T are the phosphorylable residues. More subtle AKT preferences were also uncovered for other residues surrounding the phosphorylation site, such as a preference for T at -2 or a bulky hydrophobic residue at +1 (Manning et al., 2007). More than 400 different proteins containing the consensus sequence for AKT phosphorylation have been identified, also if many of them still have to be characterized (Nicholson et al., 2002; Obenauer et al., 2003). The heterogeneity of proteins potentially phosphorylated by AKT supports the key role of this kinase. Over 100 non-redundant AKT substrates are reported in the literature, of which 25% do not contain the minimal requirements for an AKT site. Around 40 substrates which mediate the pleiotropic AKT functions have been characterized (see table below).

Apoptosis inhibition. Survival factors can suppress apoptosis and enhance survival of cells by activating AKT, which inactivates components of the apoptotic machinery. AKT directly regulates apoptosis by phosphorylating and inactivating pro-apoptotic proteins such as bad, which controls release of cytochrome c from mitochondria, caspase-9, which after AKT dependent phosphorylation promotes cell survival (Donepudi et al., 2002; Downward et al., 1999; Franke et al., 2003) and apoptosis signal-regulating kinase-1 (ASK1), a mitogen-activated protein kinase involved in stress- and cytokine-induced cell death that, once phosphorylated on serine 83, reduces apoptosis (Autret et al., 2008; Datta et al., 1997; Del Peso et al., 1997; Zha et al., 1996). The pro-survival proline-rich AKT substrate of 40kDa (PRAS40) can be phosphorylated on threonine 246, attenuating its ability to inhibit mTORC1 kinase activity (Van der Haar, 2007). PRAS40 appears to protect neuronal cells from apoptosis after stroke (Kovacina et al., 2003) and has been proposed to promote cell survival in cancer cells (Huang et al., 2005).

Proliferation. AKT can stimulate cell cycle progression through the inhibitory phosphorylation of the cyclin-dependent kinase inhibitors p21 and p27 (Viglietto et al., 2002; Liang et al., 2002; Shin et al., 2002; Zhou et al., 2001; Rossig et al., 2001). The AKT dependent inhibition of GSK3 stimulates cell cycle progression by stabilizing cyclin D1 expression (Diehl et al., 1998). AKT activation can promote progression through mitosis, even in the presence of DNA damage (Kandel et al., 2002); a mechanism explaining this observation is that AKT directly phosphorylates the DNA damage checkpoint kinase Chk1 on serine 280 (King et al., 2004), blocking checkpoint function by stimulating Chk1 translocation to the cytosol. With no K protein kinase-1 (WNK1) seems to be a negative regulatory element in the insulin signaling pathway that regulates cell proliferation. AKT phosphorylates WNK1 on threonine 60 within the AKT consensus sequence (Vitari et al., 2004). The neurofibromatosis-2 (NF2) tumour-suppressor gene encodes an intracellular membrane-associated protein, called merlin, with growth-suppressive function. AKT phosphorylates merlin on threonine 230 and serine 315 residues, abolishing binding partners and leading to merlin degradation by ubiquitination (Tang et al., 2007).

Metabolism. AKT phosphorylates the GSK3alpha and GSK3beta isoforms, which are involved in metabolism regulation by decreasing glycogen synthesis and increasing glycolytic enzymes transcription (Jope et al., 2004; Kohn et al., 1996), thus relating AKT activation with high glycolysis efficiency in cancer cells (Warburg effect). AKT1 is also involved in tolerance of cells to nutrient depletion, allowing tumor progression under hypovascular conditions (Izuishi et al., 2000). The TBC1 domain family member 1 (TBC1D1), AKT substrate phosphorylated on threonine 590, may be involved in controlling GLUT1 glucose transporter expression through the mTOR/p70S6K pathway (Zhou et al., 2008). The Rab-GAP AS160 (also known as TBC1D4) has emerged as an important direct target of AKT involved in GLUT4 translocation to the plasma membrane (Sano et al., 2003). In hepatocytes, AKT can also inhibit gluconeogenesis and fatty acid oxidation through direct phosphorylation on serine 570 of PGC-1alpha (Li et al., 2007), which is a gene coactivator with FoxO1 and other transcription factors.

Angiogenesis. AKT plays important roles in angiogenesis through effects in both endothelial cells and cells producing angiogenic signals. AKT activates endothelial nitric oxide synthase (eNOS) through direct phosphorylation on the serine 1179 site, resulting in increased production of nitric oxide (NO) in vascular endothelium, which stimulates vasodilatation, vascular remodelling and angiogenesis (Iantorno et al., 2007).

Translation. A well known AKT substrate is the serine/threonine kinase mammalian target of rapamycin (mTOR), which controls the translation of several proteins important for cell cycle progression and growth (Starkman et al., 2005; Varma et al., 2007). AKT can directly phosphorylate and activate mTOR, as well as cause indirect activation of mTOR by phosphorylating two sites on the tuberous sclerosis complex 2 (TSC2) tumour suppressor protein, also called tuberin (Manning et al., 2002). mTOR forms two complexes : TORC1 , in which mTOR is bound to Raptor, and TORC2, in which mTOR is bound to Rictor. In the TORC1 complex, mTOR signals to its downstream effectors S6 kinase/ribosomal protein and 4EBP-1/eIF-4E to control protein translation. In the TORC2 complex, mTOR can phosphorylate AKT itself thus providing a positive feedback on the pathway (Sarbassov et al., 2005). The mTOR effector S6 kinase-1 (S6K1) can also regulate the pathway by inhibiting the insulin receptor substrate (IRS), thus preventing IRS proteins from activating the PI3K/AKT signaling (Harrington et al., 2004; Shah et al., 2004). The Y box-binding protein 1 (YB-1) is a DNA/RNA-binding protein through the Y-box motif in target sequences. AKT phosphorylates YB-1 on serine 102, leading to an enhancement of cap-dependent translation of multidrug resistance 1 (MDR1) gene (Bader et al., 2008).

Nuclear functions. Among the AKT substrates identified into cell nucleus, acinus is a nuclear factor required for chromatin condensation which induces resistance to caspases proteolysis and to apoptosis when phosphorylated by AKT on serine 422 and 573 (Hu et al., 2005). Phosphorylation of the murine double minute 2 (MDM2/HDM2 in humans) oncogene by AKT promotes its translocation to the nucleus, where it negatively regulates p53 function with subsequent modification of the cell cycle in relation to DNA repair mechanisms (Vousden et al., 2002; Mayo et al., 2005). Several Akt substrates are nuclear transcription factors: AKT blocks forkhead transcription factors (FKHR/FOXO1) and in particular the FoxO subfamily-mediated transcription of genes that promote apoptosis, cell cycle arrest and metabolic processes. When phosphorylated by AKT, FKHR are sequestrated in the cytoplasm thus inhibiting transcription (Nicholson et al., 2002; Datta et al., 1997). AKT can phosphorylate IKK, indirectly increasing the activity of nuclear factor kappa B (NF-kB), which stimulates the transcription of pro-survival genes and regulates the immunity response (Ozes et al., 1999; Romashkova et al., 1999; Verdu et al., 1999). The cAMP-response element binding protein (CREB) is a direct target for phosphorylation by AKT, occurring on a site that increases binding of CREB to proteins necessary for induction of genes containing cAMP responsive elements (CREs) in their promoter regions; CREB has been shown to mediate AKT-induced expression of antiapoptotic genes bcl-2 and mcl-1 (Du et al., 1998). AKT can regulate the telomerase activity necessary for DNA replication; recombinant AKT was found to enhance telomerase activity by phosphorylating the human telomerase reverse transcriptase (hTERT) subunit, which contains a consensus motif as AKT substrate. The helix-loop-helix transcription factor tal1, required for blood cell development, is specifically phosphorylated by AKT at threonine 90, causing its nuclear redistribution (Palamarchuk et al., 2005b). Insulin induces GATA2 phosphorylation on serine 401 by AKT. GATA2 transcription factor is an inhibitor of adipogenesis and activator of vascular cells. AHNAK is a protein of exceptionally large size localized into nuclei and able to shuttle between nucleus and cytoplasm; it is downregulated in several tumors (Amagai et al., 2004). It has been reported that in epithelial cells its extranuclear localization is regulated by AKT dependent phosphorylation (Sussman et al., 2001). ALY is a nuclear speckle protein implicated in mRNA export. The PI3K/AKT signaling regulates its subnuclear residency, cell proliferation, and mRNA export activities through nuclear AKT dependent phosphorylation on threonine 219 and phosphoinositide association (Okada et al., 2008). AKT specifically phosphorylates serine 350 of the Nur77 protein within its DNA-binding domain, decreasing its transcriptional activity by 50-85% and connecting the AKT axis with a nuclear receptor pathway (Pekarsky et al., 2001). The breast cancer susceptibility gene BRCA1 encodes a nuclear phosphoprotein that acts as a tumor suppressor; heregulin induces AKT-dependent phosphorylation of BRCA1, which has been implicated in altering its function (Altiok et al., 1999).

 
  * substrates assessed independently by multiple reports (Manning et al., 2007).
Homology Homologs. AKT belongs to the AGC protein kinase family, sharing a high similarity in the catalytic domain with more than 80 kinases from the AGC family (PhosphositePlus). Three isoforms, AKT1, AKT2 and AKT3, plus a fourth isoform defined AKTgamma1, have been identified in humans. They are codified by different genes with 80% sequence homology. The AKT isoforms share 80% homology in amino acid sequence. In particular, the identity between each domain of the AKT isoforms ranges from 76% to 84% in the PH domain, from 87% to 90% in the catalytic domain, and from 66% to 76% in the C-terminal domain (Masure et al., 1999; Kumar et al., 2005). The AKT isoforms are identical in the ATP binding region, except for one residue: AKT1 A230 is conserved in AKT2 (A232), but switches in AKT3 (V228).

Orthologs. AKT is evolutionarily conserved in eukaryotes ranging from Caenorhabditis elegans to man. The amino acid identity between C. elegans and human AKT1 is around 60%; the mouse AKT1 is 90% homologous to human AKT1 at the nucleic acid level and 98% homologous at the amino acid level (Hanada et al., 2004; Bellacosa et al., 1993).
For details see : HomoloGene.
Also the phosphorylation sites on the AKT substrates are conserved amongst the orthologs from all mammals; this evolutionary conservation can be indicative of the relevance of the substrate toward the AKT cellular functions.

 

Mutations

Note Although mutation of AKT1 is rare, different types of AKT1 alterations are involved in several human diseases, especially in cancer.
No AKT1 mutations have been collected in the COSMIC database.
 
  Schematic representation of SNPs and point mutation in the AKT1 gene. Missense (red), synonymous (green) and frameshift (blue) SNPs are indicated in the upper part; point mutation is reported in the lower part of the figure.
For details see: Single Nucleotide Polymorphism.
Germinal No germline mutations of AKT1 have been described.
Somatic Amplification and LOH. Amplification of AKT1 has been described in human gastric adenocarcinoma, in lung and other cancers (Staal, 1987; Lockwood et al., 2008).
High level amplification in breast tissues and LOH in several tissues have been reported: CONAN: Copy Number Analysis.
SNPs. 17 esonic variations (missense, synonymous and frameshift SNPs) have been described.
Moreover, statistical significance for single markers and multilocus haplotypes has been reported for the association between the AKT1 gene variants in samples of families with schizophrenia using single-nucleotide polymorphisms (Schwab et al., 2005; Emamian et al., 2004).
Point mutation. The E17K mutation occurs in the lipid-binding pocket of AKT1 PH domain. Lysine 17 alters the electrostatic interactions of the pocket and forms new hydrogen bonds with a phosphoinositide ligand. This mutation activates AKT1 by means of pathological localization to the plasma membrane, stimulates downstream signaling, transforms cells and induces leukemia in mice. The E17K mutation occurs in a small percentage of human breast, ovarian, and colorectal cancers (Carpten et al., 2007). It has been found also in squamous cell carcinoma of the lung and in prostate cancer (Malanga et al., 2008; Boormans et al., 2008). Some authors suggested that this mutation may not play a crucial role in the development of the most types of human cancers (Kim et al., 2008).

Implicated in

Entity Various cancers
Prognosis Immunohistochemical analysis has been used to demonstrate prognostic significance of AKT1 activation. Phosphorylation of AKT1 at serine 473 has been associated with poor prognosis in cancer of the skin (Dai et al., 2005), pancreas (Yamamoto et al., 2004), liver (Nakanishi et al., 2005), prostate (Kreisberg et al., 2004), breast (Perez-Tenorio et al., 2002), endometrium (Terakawa et al., 2003), stomach (Nam et al., 2003), brain (Ermoian et al., 2002) and blood (Min et al., 2004). It has been reported that AKT phosphorylation on both serine 473 and threonine 308 sites is a better predictor of poor prognosis in tumors versus normal tissues than serine 473 alone (Tsurutani et al., 2006; Kornblau et al., 2006).
Oncogenesis The PI3K/AKT pathway is a prototypic survival signaling that is constitutively activated in many types of cancer, due to AKT gene amplification or as a result of mutations in components of the signaling that activates AKT. Once activated, signaling through AKT can be propagated to a diverse array of substrates. This pathway is an attractive therapeutic target in cancer because it serves as a convergence point for many growth stimuli, and through its downstream substrates, controls cellular processes that contribute to cancer progression. Moreover, activation of the PI3K/AKT pathway confers resistance to many types of cancer therapy, and is poor prognostic factor for several tumors. Thus, combining conventional therapy with PI3K/AKT pathway inhibitors can overcome this resistance.
Hyper-activation of AKT1 has been found associated to several human cancers:
-Thyroid carcinoma
-Breast carcinoma
-Non-small cell lung carcinoma
-Gastric carcinoma
-Gastro-intestinal stromal tumors
-Pancreatic carcinoma
-Bile duct carcinoma
-Ovarian carcinoma
-Prostate carcinoma
-Renal cell carcinoma
-Acute and chronic leukemia
-Multiple myeloma
-Lymphoma
  
Entity Thyroid cancer
Note Genetic alterations in the AKT pathway have been observed in anaplastic and follicular thyroid cancers, in particular AKT has been shown highly phosphorylated in thyroid cancer cell lines and human thyroid cancer specimens (Liu et al., 2008; Mandal et al., 2005). Activated AKT is common to both human and mouse follicular thyroid cancer and is correlated with increased cell motility in vitro and metastasis in vivo (Kim et al., 2005).
  
Entity Breast cancer
Note Somatic mutation E17K occurs in the PH domain of AKT1 in 8% of human breast cancers (Carpten et al., 2007). Overexpression of cyclin D1 has been found in breast cancer; elevated cyclin D1 levels result in shortened cell cycle times and thereby contribute to tumor progression. AKT is involved in this mechanism by regulating cyclin D1 expression at transcription, translation and protein stability level (Nicholson et al., 2002). Anti-estrogens such as tamoxifen inhibit the growth of (estrogens receptors) ER-positive breast cancers by reducing the expression of estrogen-regulated genes. AKT, by activating ER, protects breast cancer cells from tamoxifen-induced apoptosis (Campbell et al., 2001). It has been shown that activation of AKT/mTOR promotes angiogenesis via HIF1alpha stabilization in breast cancer cells (Laughner et al., 2001). Recent studies have shown that AKT1 can attenuate breast cancer cell motility, whereas AKT2 enhances this phenotype. AKT1 blocks the migration of breast cancer cells through GSK3beta inactivation and transcription factor NFAT inhibition (Yoeli-Lerner et al., 2009).
  
Entity Lung cancer
Note Although AKT1 mutations are apparently rare in lung cancer (1.9%), the oncogenic properties of E17K-AKT1 may contribute to the development of a fraction of lung carcinoma with squamous histotype (Malanga et al., 2008). Adenocarcinomas of the lung commonly show an increase in the activity of PI3K/AKT signaling pathway. The simultaneous inhibition AKT1 siRNA and Bcl-xL function greatly enhanced the apoptotic response, suggesting that AKT1 and Bcl-xL control cell death in lung adenocarcinoma cells in a synergistic manner (Qian et al., 2009). AKT1 is overexpressed as a direct result of gene amplification in lung cancer, suggesting that amplification of this genome hotspot is a common mechanism of oncogene activation (Lockwood et al., 2008).
  
Entity Gastric carcinoma
Note AKT1 gene amplification has been observed in gastric carcinoma. Most gastric adenocarcinomas arise as a longterm complication of Helicobacter pylori infection of the stomach; phosphorylation of AKT and its substrates is inducible by epithelial mitogens such as EGF, which is implicated in the pathogenesis of H. pylori gastritis (Ang et al., 2005). NF-KB activation was frequently observed in early-stage gastric carcinoma and was significantly correlated with better prognosis and Akt activation (Lee et al., 2005). AKT activation and LOH of PTEN play an important role in conferring a broad-spectrum chemoresistance in gastric cancer patients (Oki et al., 2005).
  
Entity Colorectal cancer
Note The transforming E17K point mutation in the PH domain of AKT1 in human colorectal cancer (6%) has been identified (Carpten et al., 2007). The Src/PI3K/FAK/AKT pathway has been described as responsible of colon cancer cells metastatic adhesion (Thamilselvan et al., 2007). Cytoplasmic mislocalization of p27, caused by activated AKT1, and functional losses of p27 and p53 have been associated with poor prognosis and are involved in the development of various subtypes of colorectal cancer (Ogino et al., 2007). The inhibitor of the apoptosis protein (IAP) family member XIAP is essential for cell survival in colorectal cancer cells and is activated through the AKT pathway. The AKT-XIAP up-regulation was shown to be correlated to colorectal cancer progression and may be a potential molecular target for therapy (Takeuchi et al., 2005).
  
Entity Glioblastoma and gliosarcoma
Note AKT1 amplification and overexpression have been observed in human glioblastoma and gliosarcoma, a variant of glioblastoma multiforme characterized by two components displaying gliomatous or sarcomatous differentiation (Actor et al., 2002; Staal et al., 1987). Glioblastomas frequently carry mutations in PTEN gene, which tumor suppressor properties are closely related to its inhibitory effect on the AKT signaling (Knobbe et al., 2003).
  
Entity Pancreatic cancer
Note It was reported that constitutively active AKT1 in mouse pancreas requires S6 kinase 1 for insulinoma formation (Alliouachene et al., 2008). AKT1 serine 473 may undergo both phosphorylation and O-GlcNAc modification, and the balance between these events may regulate murine beta-pancreatic cell apoptosis (Kang et al., 2008). All the AKT isoforms may have protective effects within the cell depending on the type of apoptotic stimuli in human pancreatic MiaPaCa-2 cells (Han et al., 2008). Overexpression of bcl-2 is common in pancreatic cancer, confers resistance to the apoptotic effect of chemo- and radiotherapy and is accompanied to increased activity of AKT as well as its downstream target IKK (Mortenson et al., 2007).
  
Entity Hepatocellular carcinoma (HCC)
Note Hyper-activation of the AKT pathway frequently occurs in HCC (Roberts et al., 2005). It was reported that Bortezomib induces apoptosis in HCC cell lines by down-regulating phospho-AKT. Down-regulation of phospho-AKT may thus represent a biomarker for predicting clinical response to HCC treatment (Chen et al., 2008). Moreover, it was observed that a cancer stem cell population in HCC contributes to chemoresistance through preferential activation of AKT and bcl-2 cell survival response (Ma et al., 2008). Knockdown of insulin receptor substrate in primary human HCC HepG2 cell line resulted in reduction of insulin stimulated AKT1 phosphorylation at serine 473 and 50% reduction in the basal level of phosphorylated mTOR (Ser 2448), indicating a pivotal role of the AKT signaling in HCC (Varma et al., 2008). It was also presented that AKT1 was upregulated in HCC cells, and its active phosphorylated form was mainly located in the nucleus (Zhu et al., 2007).
  
Entity Ovarian cancer
Note The transforming E17K point mutation in the PH domain of AKT1 in human ovarian cancer (2%) has been identified (Carpten et al., 2007). The AKT pathway plays an important role in cell proliferation, migration, and invasion in ovarian cancer cells; particular importance has the signaling specificity of AKT1, as the inhibition of AKT1 is sufficient to affect these events (Meng et al., 2006; Kim et al., 2008; Gu et al., 2008).
  
Entity Prostate cancer
Note Increased AKT1 kinase activity was reported in more than 50% of prostate carcinomas. The androgen receptor (AR) factors phosphorylated by AKT lead to inhibition of their activity and blockade of androgen-induced apoptosis in a prostate cancer cell line (Lin et al., 2001). A study of prostate cancer indicates that AKT is involved more in cancer progression than initiation. The E17K mutation was identified in clinical prostate cancer samples. The mutation was mutually exclusive with respect to PTEN inactivation and PI3K activation; it was suggested that tumors carrying the AKT1 mutation may follow a more favourable clinical course (Boormans et al., 2008).
  
Entity Renal cancer
Note Phospho-AKT expression is significantly increased in renal carcinoma cells. A decreased expression of PTEN may be an underlying mechanism for AKT activation and thus an AKT inhibitor may be a therapeutic option for the subset of renal cell carcinoma patients with elevated AKT activity (Hara et al., 2005).
  
Entity Melanoma
Note Common mutations and/or deregulated expression of proteins of the AKT signaling, as B-RAF, PTEN, MDM2 and AKT itself, were identified in melanoma (Ch'ng et al., 2009). AKT-dependent phosphorylation of hTERT increases telomerase activity in melanoma cells, indicating that AKT promotes the immortalization of cancer cells by preventing replicative senescence (Kang et al., 1999).
  
Entity Acute leukemia
Note The AKT signaling is important for governing cell survival and proliferation in acute myeloid leukemia (AML). The level of AKT phosphorylation on threonine 308 but not on serine 473 is associated with high-risk cytogenetics and predicts poor overall survival in AML (Gallay et al., 2009). AKT activation critically mediates survival during the early phase of drug (i.e. imatinib) resistance development (Burchert et al., 2005). PTEN phosphorylation, associated with increased AKT phosphorylation, is found in 75% of AML (Cheong et al., 2003a). Also SHIP1 alteration is shown to result in AKT activation in AML cells (Luo et al., 2003). AKT constitutive activation is observed in more than 50% of AML cases and correlates with chemotherapy resistance and poor prognosis (Min et al., 2003; Grandage et al., 2005; Martelli et al., 2007). In acute leukemias, AKT activation gives rise to the upregulation of several downstream targets as FoxO transcription factors in AML patients with poor prognosis (Tamburini et al., 2007; Cheong et al., 2003b), Bad, p27, GSK3beta, IKK, p70S6K and 4E-BP1 in AML blasts (Zhao et al., 2004; Guzman et al., 2001; Xu et al., 2003).
AKT signaling plays an important role in cell survival mechanisms in acute promyelocytic leukemia (APL) (Billottet et al., 2009); recent advances have defined a novel PML/PTEN/AKT/mTOR/FoxO signaling network (Ito et al., 2009). The promyelocytic leukemia protein (PML) has established activities as a potent repressor of proliferation and oncogenic transformation, a promoter of apoptosis, an inducer of senescence, and may act as angiogenesis inhibitor. PML tumour suppressor prevents cancer by inactivating phospho-AKT inside the nucleus and suppressing apoptotic rescue (Culjkovic et al., 2008).
In acute lymphoblastic leukemia (ALL) cell lines such as Jurkat T cells, PTEN is deleted thus activating the AKT pathway and promoting survival (Xu et al., 2002; Uddin et al., 2004). In addition, an activating mutation of Notch1 receptor in ALL cells is found to inhibit PTEN expression with subsequent AKT activation (Palomero et al., 2007).
  
Entity Chronic leukemia
Note Chronic myelogenous leukemia (CML) is caused by BCR-ABL fusion gene product, that has constitutive tyrosine kinase activity and evokes the PI3K/AKT signaling pathway (Steelman et al., 2004). AKT is constitutively active in primary CML cells of both the chronic phase and blast crisis as well as in CML cell lines (Kawauchi et al., 2003). Introduction of a dominant-negative kinase-deficient AKT mutant (K179M) inhibits leukemogenesis in murine cells, indicating an important role of AKT in transformation with BCR-ABL through the possible effectors FoxO, MDM2, GSK3beta, S6K and 4EBP-1 (Skorski et al, 1997; Kharas et al., 2005). Furthermore, AKT-dependent phosphorylation of FoxO3A is required for maintaining the leukemic phenotype (Birkenkamp et al., 2007).
  
Entity Myeloma
Note In both myeloma cell lines and primary cells IL-6 and IGF-1 activate the PI3K/AKT pathway accompanied by enhanced phosphorylation of downstream targets such as Bad, GSK3beta, and FoxO (Hideshima et al., 2001; Tu et al., 2000; Hsu et al., 2002). The expression of CD45 in myeloma cells negatively regulates the responsiveness to IGF-1 stimulation that leads to AKT activation (Descamps et al., 2004). Furthermore, IL-6 and IGF-1 both upregulate telomerase activity, which is usually coupled with cell division, mediated by AKT signaling (Akiyama et al., 2002). Constitutive phosphorylation of AKT has been reported in primary samples from patients with myeloma (Pene et al., 2002). In addition, inhibition of mTOR induces prevention in tumor proliferation and angiogenesis in myeloma cells associated with high levels of AKT activation (Frost et al., 2004).
  
Entity Lymphomas
Note AKT activation has been demonstrated in a variety of B-cell non-Hodgkin's lymphomas (NHL) including Follicular Lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), marginal zone B-cell lymphoma and Mantle Cell Lymphoma (MCL) (Rudelius et al., 2006; Dal Col et al., 2008). Constitutive phosphorylation of AKT on serine 473 has been found also in peripheral leukemia cells of T-cell large granular lymphocytic leukemia (T-LGL) (Schade et al., 2006). Constitutive phosphorylation of AKT, GSK3beta, and mTOR substrates such as S6K and 4E-BP1 was demonstrated in Hodgkin's lymphoma (HL) cell lines, suggesting that the AKT pathway plays a crucial role in survival of HL cells (Dutton et al., 2005). Moreover, proteomic analysis of FL tissues showed overexpression of phospho-AKT on serine 473 (Gulman et al., 2005). In primary DLBCL samples, there is a correlation between poor prognosis and constitutive activation of AKT (Uddin et al., 2006; Ogasawara et al., 2003). In primary samples from anaplastic large cell lymphoma (ALCL) patients, around half of ALCLs exhibit constitutive phosphorylation of AKT on serine 473 and the AKT target p27 is downregulated in ALCL cell lines (Rassidakis et al., 2005). Moreover, mTOR, S6K and 4E-BP1 are constitutively phosphorylated in cell lines and in tissue samples from ALCL patients (Vega et al., 2006), indicating that the AKT pathway may be implicated in cell proliferation and survival of ALCL tumors. AKT and its downstream targets, including GSK3, FoxO3A, p27, MDM2, Bad, p70S6K and 4E-BP1, have been shown to be constitutively phosphorylated in both primary MCL cells and MCL cell lines (Rudelius et al., 2006). AKT is likely to be more active in blastoid MCL variants than in typical MCL, suggesting that the AKT pathway plays a critical role in pathogenesis in aggressive MCL cases. Constitutive AKT activation has been demonstrated in adult T-cell leukemic (ATL) cells as well as in ATL cell lines. HSP90, a chaperone protein for AKT, and the mTOR pathway are required for cell proliferation and survival in primary ATL samples, suggesting a crucial role for the AKT/mTOR axis in ATL expansion (Kawakami et al., 2007). B-cell antigen receptor (BCR) stimulation has been shown to induce AKT phosphorylation on serine 473 (Poggi et al., 2008; Longo et al., 2007). In addition, CpG-oligodeoxynucleotide (CpG-ODN) stimulates leukemia cell proliferation accompanied by upregulation of AKT phosphorylation on 473 residue in B-CLL patients with poor prognosis (Longo et al., 2008). Therefore, AKT activation seems to be involved in CLL B-cell expansion.
  
Entity Various diseases
Note Alteration of AKT activity is associated with several human diseases, including atherosclerosis, cardiovascular disease, Alzheimer disease, schizophrenia and diabetes.
  
Entity Atherosclerosis
Note Oxidized low-density lipoproteins LDLs activate the PI3K/AKT network in macrophages/foam cells (Biwa et al., 2000). The amount of phosphorylated AKT and other phosphorylated effector proteins as S6K, S6, GSK3beta and FKHR was found to be reduced in atherosclerotic lesions.
  
Entity Cardiovascular disease
Note The first report on a role of the PI3K/AKT pathway in the control of cell and organ size was published more than 10 years ago (Leevers et al., 1996). AKT signaling is relayed via mTOR to control the heart size. The cardiomyocyte-specific inactivation of the lipid phosphatase PTEN and subsequent AKT hyper-activation also triggers heart hypertrophy and culminates in reduced cardiac contractility (Crackower et al., 2002). AKT is involved in the therapy for ischemic limb or heart (Huang et al., 2009; Kruger et al., 2009). Moreover, long-term activation of AKT/mTOR signaling links diet-induced obesity with vascular senescence and cardiovascular disease (Wang et al., 2009).
  
Entity Alzheimer disease
Note Microtubule-associated protein tau contains a consensus motif for AKT encompassing the double phospho-epitope (T212/S214). AKT dependent phosphorylation of tau occurs in vitro at both threonine 212 and serine 214 and may play specific roles relevant to Alzheimer disease and other neurodegenerations (Ksiezak-Reding et al., 2003). Modulators of the PI3K pathway might be reduced during aging leading to a sustained activation of GSK3beta, which in turn would increase the risk of tau hyper-phosphorylation (Mercado-Gomez et al., 2008). In primary cultures, AKT selectively phosphorylates tau at serine 214, raising the possibility that 214 residue may participate in AKT-mediated anti-apoptotic signaling (Kyoung Pyo et al., 2004).
  
Entity Schizophrenia
Note Association between schizophrenia and an AKT1 haplotype associated with lower AKT1 levels and a greater sensitivity to the sensorimotor gating-disruptive effect of amphetamine, conferred by AKT1 deficiency, has been described. Alterations in AKT1/GSK3beta signaling contribute to schizophrenia pathogenesis and AKT1 gene may confer potential schizophrenia susceptibility. Consistent with this proposal, it has been shown that haloperidol induces a stepwise increase in regulatory phosphorylation of AKT1 in the brains of treated mice, that could compensate for an impaired function of this signaling pathway in schizophrenia (Emamian et al., 2004).
  
Entity Diabetes type 2
Note AKT is involved in the pathomechanism of diabetes as it determines beta-cell apoptosis of Langerhans islets and insulin sensitivity of the cells (Cseh et al., 2009; Schulthess et al., 2009). It has been reported that alterations of the AKT/mTOR or the AKT/PRAS40 axis contributes to a diabetic phenotype (Marshall et al., 2006; Nascimento et al., 2006). AKT is required for the metabolic actions of insulin; muscle cells from type 2 diabetic patients displayed defective insulin action and a drastic reduction of insulin-stimulated activity of all AKT isoforms, in particular with altered AKT1 phosphorylation on threonine 308 residue (Cozzone et al., 2008). Insulin resistance can be induced by stimulating the degradation of important molecules in the insulin signaling pathway as AKT1 (Wing et al., 2008).
  

External links

Nomenclature
HGNC (Hugo)AKT1   391
Cards
AtlasAKT1ID355ch14q32
Entrez_Gene (NCBI)AKT1  207  v-akt murine thymoma viral oncogene homolog 1
GeneCards (Weizmann)AKT1
Ensembl (Hinxton)ENSG00000142208 [Gene_View]  chr14:105235687-105262080 [Contig_View]  AKT1 [Vega]
AceView (NCBI)AKT1
Genatlas (Paris)AKT1
WikiGenes207
SOURCE (Princeton)NM_001014431 NM_001014432 NM_005163
Genomic and cartography
GoldenPath (UCSC)AKT1  -  14q32.33   chr14:105235687-105262080 -  14q32.32-q32.33   [Description]    (hg19-Feb_2009)
EnsemblAKT1 - 14q32.32-q32.33 [CytoView]
Mapping of homologs : NCBIAKT1 [Mapview]
OMIM114480   114500   164730   167000   176920   181500   604370   615109   
Gene and transcription
Genbank (Entrez)AB451242 AB451367 AK094287 AK122894 AK131465
RefSeq transcript (Entrez)NM_001014431 NM_001014432 NM_005163
RefSeq genomic (Entrez)AC_000146 NC_000014 NC_018925 NG_012188 NT_026437 NW_001838116 NW_004929393
Consensus coding sequences : CCDS (NCBI)AKT1
Cluster EST : UnigeneHs.525622 [ NCBI ]
CGAP (NCI)Hs.525622
Alternative Splicing : Fast-db (Paris)GSHG0009653
Alternative Splicing GalleryENSG00000142208
Gene ExpressionAKT1 [ NCBI-GEO ]     AKT1 [ SEEK ]   AKT1 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP31749 (Uniprot)
NextProtP31749  [Medical]
With graphics : InterProP31749
Splice isoforms : SwissVarP31749 (Swissvar)
Catalytic activity : Enzyme2.7.11.1 [ Enzyme-Expasy ]   2.7.11.12.7.11.1 [ IntEnz-EBI ]   2.7.11.1 [ BRENDA ]   2.7.11.1 [ KEGG ]   
Domaine pattern : Prosite (Expaxy)AGC_KINASE_CTER (PS51285)    PH_DOMAIN (PS50003)    PROTEIN_KINASE_ATP (PS00107)    PROTEIN_KINASE_DOM (PS50011)    PROTEIN_KINASE_ST (PS00108)   
Domains : Interpro (EBI)AGC-kinase_C    Kinase-like_dom    PH_like_dom    Pkinase_C    Pleckstrin_homology    Prot_kinase_dom    Protein_kinase_ATP_BS    Ser/Thr_dual-sp_kinase_dom    Ser/Thr_kinase_AS   
Related proteins : CluSTrP31749
Domain families : Pfam (Sanger)PH (PF00169)    Pkinase (PF00069)    Pkinase_C (PF00433)   
Domain families : Pfam (NCBI)pfam00169    pfam00069    pfam00433   
Domain families : Smart (EMBL)PH (SM00233)  S_TK_X (SM00133)  S_TKc (SM00220)  
DMDM Disease mutations207
Blocks (Seattle)P31749
PDB (SRS)1H10    1UNP    1UNQ    1UNR    2UVM    2UZR    2UZS    3CQU    3CQW    3MV5    3MVH    3O96    3OCB    3OW4    3QKK    3QKL    3QKM    4EJN    4EKK    4EKL    4GV1   
PDB (PDBSum)1H10    1UNP    1UNQ    1UNR    2UVM    2UZR    2UZS    3CQU    3CQW    3MV5    3MVH    3O96    3OCB    3OW4    3QKK    3QKL    3QKM    4EJN    4EKK    4EKL    4GV1   
PDB (IMB)1H10    1UNP    1UNQ    1UNR    2UVM    2UZR    2UZS    3CQU    3CQW    3MV5    3MVH    3O96    3OCB    3OW4    3QKK    3QKL    3QKM    4EJN    4EKK    4EKL    4GV1   
PDB (RSDB)1H10    1UNP    1UNQ    1UNR    2UVM    2UZR    2UZS    3CQU    3CQW    3MV5    3MVH    3O96    3OCB    3OW4    3QKK    3QKL    3QKM    4EJN    4EKK    4EKL    4GV1   
Human Protein AtlasENSG00000142208
Peptide AtlasP31749
HPRD01261
IPIIPI00012866   IPI01009564   IPI01026058   IPI01025286   IPI01025645   IPI01025067   
Protein Interaction databases
DIP (DOE-UCLA)P31749
IntAct (EBI)P31749
FunCoupENSG00000142208
BioGRIDAKT1
InParanoidP31749
Interologous Interaction database P31749
IntegromeDBAKT1
STRING (EMBL)AKT1
Ontologies - Pathways
Ontology : AmiGOprotein import into nucleus, translocation  osteoblast differentiation  maternal placenta development  positive regulation of protein phosphorylation  protein kinase activity  protein serine/threonine kinase activity  protein serine/threonine kinase activity  protein kinase C binding  protein binding  ATP binding  ATP binding  phosphatidylinositol-3,4,5-trisphosphate binding  nucleus  nucleus  nucleoplasm  cytoplasm  cytoplasm  cytoplasm  spindle  cytosol  cytosol  plasma membrane  plasma membrane  glycogen biosynthetic process  regulation of glycogen biosynthetic process  glucose metabolic process  translation  regulation of translation  cellular protein modification process  protein phosphorylation  negative regulation of protein kinase activity  negative regulation of protein kinase activity  nitric oxide biosynthetic process  apoptotic process  activation-induced cell death of T cells  inflammatory response  signal transduction  epidermal growth factor receptor signaling pathway  G-protein coupled receptor signaling pathway  germ cell development  aging  blood coagulation  cell proliferation  insulin receptor signaling pathway  fibroblast growth factor receptor signaling pathway  apoptotic mitochondrial changes  response to heat  gene expression  negative regulation of autophagy  negative regulation of plasma membrane long-chain fatty acid transport  positive regulation of sodium ion transport  positive regulation of glucose metabolic process  negative regulation of endopeptidase activity  regulation of neuron projection development  microtubule cytoskeleton  glucose transport  RNA metabolic process  mRNA metabolic process  kinase activity  phosphorylation  protein ubiquitination  peptidyl-serine phosphorylation  enzyme binding  lamellipodium  cell projection organization  cell differentiation  protein catabolic process  platelet activation  nitric-oxide synthase regulator activity  positive regulation of cell growth  regulation of cell migration  regulation of cell migration  endocrine pancreas development  T cell costimulation  positive regulation of cyclin-dependent protein serine/threonine kinase activity involved in G1/S transition of mitotic cell cycle  negative regulation of fatty acid beta-oxidation  response to food  positive regulation of cellular protein metabolic process  peripheral nervous system myelin maintenance  positive regulation of proteasomal ubiquitin-dependent protein catabolic process  cellular response to insulin stimulus  cellular response to insulin stimulus  positive regulation of peptidyl-serine phosphorylation  response to fluid shear stress  intracellular signal transduction  Fc-epsilon receptor signaling pathway  glucose homeostasis  anagen  identical protein binding  positive regulation of apoptotic process  negative regulation of apoptotic process  negative regulation of cysteine-type endopeptidase activity involved in apoptotic process  phosphatidylinositol-3,4-bisphosphate binding  protein kinase B signaling cascade  positive regulation of blood vessel endothelial cell migration  small molecule metabolic process  innate immune response  positive regulation of nitric oxide biosynthetic process  positive regulation of fat cell differentiation  positive regulation of glycogen biosynthetic process  positive regulation of glycogen biosynthetic process  negative regulation of cell size  negative regulation of proteolysis  positive regulation of vasoconstriction  positive regulation of transcription from RNA polymerase II promoter  nitric oxide metabolic process  positive regulation of glucose import  negative regulation of JNK cascade  protein autophosphorylation  positive regulation of lipid biosynthetic process  insulin-like growth factor receptor signaling pathway  neurotrophin TRK receptor signaling pathway  phosphatidylinositol-mediated signaling  regulation of nitric-oxide synthase activity  positive regulation of nitric-oxide synthase activity  positive regulation of sequence-specific DNA binding transcription factor activity  striated muscle cell differentiation  mammary gland epithelial cell differentiation  glycogen cell differentiation involved in embryonic placenta development  labyrinthine layer blood vessel development  response to UV-A  cellular response to epidermal growth factor stimulus  cellular response to hypoxia  14-3-3 protein binding  positive regulation of establishment of protein localization to plasma membrane  negative regulation of release of cytochrome c from mitochondria  intrinsic apoptotic signaling pathway  positive regulation of protein insertion into mitochondrial membrane involved in apoptotic signaling pathway  regulation of cell cycle checkpoint  negative regulation of intrinsic apoptotic signaling pathway in response to oxidative stress  negative regulation of extrinsic apoptotic signaling pathway in absence of ligand  
Ontology : EGO-EBIprotein import into nucleus, translocation  osteoblast differentiation  maternal placenta development  positive regulation of protein phosphorylation  protein kinase activity  protein serine/threonine kinase activity  protein serine/threonine kinase activity  protein kinase C binding  protein binding  ATP binding  ATP binding  phosphatidylinositol-3,4,5-trisphosphate binding  nucleus  nucleus  nucleoplasm  cytoplasm  cytoplasm  cytoplasm  spindle  cytosol  cytosol  plasma membrane  plasma membrane  glycogen biosynthetic process  regulation of glycogen biosynthetic process  glucose metabolic process  translation  regulation of translation  cellular protein modification process  protein phosphorylation  negative regulation of protein kinase activity  negative regulation of protein kinase activity  nitric oxide biosynthetic process  apoptotic process  activation-induced cell death of T cells  inflammatory response  signal transduction  epidermal growth factor receptor signaling pathway  G-protein coupled receptor signaling pathway  germ cell development  aging  blood coagulation  cell proliferation  insulin receptor signaling pathway  fibroblast growth factor receptor signaling pathway  apoptotic mitochondrial changes  response to heat  gene expression  negative regulation of autophagy  negative regulation of plasma membrane long-chain fatty acid transport  positive regulation of sodium ion transport  positive regulation of glucose metabolic process  negative regulation of endopeptidase activity  regulation of neuron projection development  microtubule cytoskeleton  glucose transport  RNA metabolic process  mRNA metabolic process  kinase activity  phosphorylation  protein ubiquitination  peptidyl-serine phosphorylation  enzyme binding  lamellipodium  cell projection organization  cell differentiation  protein catabolic process  platelet activation  nitric-oxide synthase regulator activity  positive regulation of cell growth  regulation of cell migration  regulation of cell migration  endocrine pancreas development  T cell costimulation  positive regulation of cyclin-dependent protein serine/threonine kinase activity involved in G1/S transition of mitotic cell cycle  negative regulation of fatty acid beta-oxidation  response to food  positive regulation of cellular protein metabolic process  peripheral nervous system myelin maintenance  positive regulation of proteasomal ubiquitin-dependent protein catabolic process  cellular response to insulin stimulus  cellular response to insulin stimulus  positive regulation of peptidyl-serine phosphorylation  response to fluid shear stress  intracellular signal transduction  Fc-epsilon receptor signaling pathway  glucose homeostasis  anagen  identical protein binding  positive regulation of apoptotic process  negative regulation of apoptotic process  negative regulation of cysteine-type endopeptidase activity involved in apoptotic process  phosphatidylinositol-3,4-bisphosphate binding  protein kinase B signaling cascade  positive regulation of blood vessel endothelial cell migration  small molecule metabolic process  innate immune response  positive regulation of nitric oxide biosynthetic process  positive regulation of fat cell differentiation  positive regulation of glycogen biosynthetic process  positive regulation of glycogen biosynthetic process  negative regulation of cell size  negative regulation of proteolysis  positive regulation of vasoconstriction  positive regulation of transcription from RNA polymerase II promoter  nitric oxide metabolic process  positive regulation of glucose import  negative regulation of JNK cascade  protein autophosphorylation  positive regulation of lipid biosynthetic process  insulin-like growth factor receptor signaling pathway  neurotrophin TRK receptor signaling pathway  phosphatidylinositol-mediated signaling  regulation of nitric-oxide synthase activity  positive regulation of nitric-oxide synthase activity  positive regulation of sequence-specific DNA binding transcription factor activity  striated muscle cell differentiation  mammary gland epithelial cell differentiation  glycogen cell differentiation involved in embryonic placenta development  labyrinthine layer blood vessel development  response to UV-A  cellular response to epidermal growth factor stimulus  cellular response to hypoxia  14-3-3 protein binding  positive regulation of establishment of protein localization to plasma membrane  negative regulation of release of cytochrome c from mitochondria  intrinsic apoptotic signaling pathway  positive regulation of protein insertion into mitochondrial membrane involved in apoptotic signaling pathway  regulation of cell cycle checkpoint  negative regulation of intrinsic apoptotic signaling pathway in response to oxidative stress  negative regulation of extrinsic apoptotic signaling pathway in absence of ligand  
Pathways : BIOCARTAAKT Signaling Pathway [Genes]    Apoptotic Signaling in Response to DNA Damage [Genes]    Control of skeletal myogenesis by HDAC & calcium/calmodulin-dependent kinase (CaMK) [Genes]    mTOR Signaling Pathway [Genes]    NFAT and Hypertrophy of the heart (Transcription in the broken heart) [Genes]    Skeletal muscle hypertrophy is regulated via AKT/mTOR pathway [Genes]    IL 4 signaling pathway [Genes]    Telomeres, Telomerase, Cellular Aging, and Immortality [Genes]    Inactivation of Gsk3 by AKT causes accumulation of b-catenin in Alveolar Macrophages [Genes]    Trka Receptor Signaling Pathway [Genes]    Role of nicotinic acetylcholine receptors in the regulation of apoptosis [Genes]    Role of Erk5 in Neuronal Survival [Genes]    Influence of Ras and Rho proteins on G1 to S Transition [Genes]    Phospholipids as signalling intermediaries [Genes]    Actions of Nitric Oxide in the Heart [Genes]    Hypoxia and p53 in the Cardiovascular system [Genes]    Phospholipase C Signaling Pathway [Genes]    B Cell Survival Pathway [Genes]    Regulation of eIF4e and p70 S6 Kinase [Genes]    Human Cytomegalovirus and Map Kinase Pathways [Genes]    Multiple antiapoptotic pathways from IGF-1R signaling lead to BAD phosphorylation [Genes]    Ras Signaling Pathway [Genes]    Transcription factor CREB and its extracellular signals [Genes]    Corticosteroids and cardioprotection [Genes]    The IGF-1 Receptor and Longevity [Genes]    PTEN dependent cell cycle arrest and apoptosis [Genes]    Trefoil Factors Initiate Mucosal Healing [Genes]    Regulation of BAD phosphorylation [Genes]    Inhibition of Cellular Proliferation by Gleevec [Genes]    IL-2 Receptor Beta Chain in T cell Activation [Genes]    Phosphoinositides and their downstream targets. [Genes]   
Pathways : KEGGMAPK signaling pathway    ErbB signaling pathway    Ras signaling pathway    Rap1 signaling pathway    Chemokine signaling pathway    HIF-1 signaling pathway    FoxO signaling pathway    mTOR signaling pathway    PI3K-Akt signaling pathway    Apoptosis    Adrenergic signaling in cardiomyocytes    VEGF signaling pathway    Osteoclast differentiation    Focal adhesion    Tight junction    Toll-like receptor signaling pathway    Jak-STAT signaling pathway    T cell receptor signaling pathway    B cell receptor signaling pathway    Fc epsilon RI signaling pathway    Fc gamma R-mediated phagocytosis    TNF signaling pathway    Neurotrophin signaling pathway    Cholinergic synapse    Dopaminergic synapse    Insulin signaling pathway    Progesterone-mediated oocyte maturation    Estrogen signaling pathway    Prolactin signaling pathway    Thyroid hormone signaling pathway    Adipocytokine signaling pathway    Non-alcoholic fatty liver disease (NAFLD)    Carbohydrate digestion and absorption    Chagas disease (American trypanosomiasis)    Toxoplasmosis    Tuberculosis    Hepatitis C    Hepatitis B    Measles    Influenza A    HTLV-I infection    Epstein-Barr virus infection    Pathways in cancer    Proteoglycans in cancer    Colorectal cancer    Renal cell carcinoma    Pancreatic cancer    Endometrial cancer    Glioma    Prostate cancer    Melanoma    Chronic myeloid leukemia    Acute myeloid leukemia    Small cell lung cancer    Non-small cell lung cancer   
REACTOMEAKT1
Protein Interaction DatabaseAKT1
Wikipedia pathwaysAKT1
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)AKT1
SNP (GeneSNP Utah)AKT1
SNP : HGBaseAKT1
Genetic variants : HAPMAPAKT1
1000_GenomesAKT1 
ICGC programENSG00000142208 
Cancer Gene: CensusAKT1 
Somatic Mutations in Cancer : COSMICAKT1 
CONAN: Copy Number AnalysisAKT1 
Mutations and Diseases : HGMDAKT1
OMIM114480    114500    164730    167000    176920    181500    604370    615109   
GENETestsAKT1
Disease Genetic AssociationAKT1
Huge Navigator AKT1 [HugePedia]  AKT1 [HugeCancerGEM]
Genomic VariantsAKT1  AKT1 [DGVbeta]
Exome VariantAKT1
dbVarAKT1
ClinVarAKT1
snp3D : Map Gene to Disease207
General knowledge
Homologs : HomoloGeneAKT1
Homology/Alignments : Family Browser (UCSC)AKT1
Phylogenetic Trees/Animal Genes : TreeFamAKT1
Chemical/Protein Interactions : CTD207
Chemical/Pharm GKB GenePA24684
Clinical trialAKT1
Cancer Resource (Charite)ENSG00000142208
Other databases
Probes
Litterature
PubMed499 Pubmed reference(s) in Entrez
CoreMineAKT1
iHOPAKT1

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Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L)
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Novel pharmacological approaches to the prevention and treatment of non-insulin-dependent diabetes mellitus.
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Transformation of hematopoietic cells by BCR/ABL requires activation of a PI-3k/Akt-dependent pathway.
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Downward J.
Nat Cell Biol. 1999 Jun;1(2):E33-5.
PMID 10559890
 
Akt protein kinase enhances human telomerase activity through phosphorylation of telomerase reverse transcriptase subunit.
Kang SS, Kwon T, Kwon DY, Do SI.
J Biol Chem. 1999 May 7;274(19):13085-90.
PMID 10224060
 
Cloning and characterization of a nuclear S6 kinase, S6 kinase-related kinase (SRK); a novel nuclear target of Akt.
Koh H, Jee K, Lee B, Kim J, Kim D, Yun YH, Kim JW, Choi HS, Chung J.
Oncogene. 1999 Sep 9;18(36):5115-9.
PMID 10490848
 
Integrin-linked kinase regulates phosphorylation of serine 473 of protein kinase B by an indirect mechanism.
Lynch DK, Ellis CA, Edwards PA, Hiles ID.
Oncogene. 1999 Dec 23;18(56):8024-32.
PMID 10637513
 
Molecular cloning, expression and characterization of the human serine/threonine kinase Akt-3.
Masure S, Haefner B, Wesselink JJ, Hoefnagel E, Mortier E, Verhasselt P, Tuytelaars A, Gordon R, Richardson A.
Eur J Biochem. 1999 Oct 1;265(1):353-60.
PMID 10491192
 
NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase.
Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB.
Nature. 1999 Sep 2;401(6748):82-5.
PMID 10485710
 
NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling.
Romashkova JA, Makarov SS.
Nature. 1999 Sep 2;401(6748):86-90.
PMID 10485711
 
Cell-autonomous regulation of cell and organ growth in Drosophila by Akt/PKB.
Verdu J, Buratovich MA, Wilder EL, Birnbaum MJ.
Nat Cell Biol. 1999 Dec;1(8):500-6.
PMID 10587646
 
Phosphorylation and regulation of Raf by Akt (protein kinase B).
Zimmermann S, Moelling K.
Science. 1999 Nov 26;286(5445):1741-4.
PMID 10576742
 
Granulocyte/macrophage colony-stimulating factor plays an essential role in oxidized low density lipoprotein-induced macrophage proliferation.
Biwa T, Sakai M, Shichiri M, Horiuchi S.
J Atheroscler Thromb. 2000;7(1):14-20. (REVIEW)
PMID 11425039
 
Negative regulation of the serine/threonine kinase B-Raf by Akt.
Guan KL, Figueroa C, Brtva TR, Zhu T, Taylor J, Barber TD, Vojtek AB.
J Biol Chem. 2000 Sep 1;275(35):27354-9.
PMID 10869359
 
Remarkable tolerance of tumor cells to nutrient deprivation: possible new biochemical target for cancer therapy.
Izuishi K, Kato K, Ogura T, Kinoshita T, Esumi H.
Cancer Res. 2000 Nov 1;60(21):6201-7.
PMID 11085546
 
Cellular signaling: pivoting around PDK-1.
Toker A, Newton AC.
Cell. 2000 Oct 13;103(2):185-8. (REVIEW)
PMID 11057891
 
The phosphatidylinositol 3-kinase/AKT kinase pathway in multiple myeloma plasma cells: roles in cytokine-dependent survival and proliferative responses.
Tu Y, Gardner A, Lichtenstein A.
Cancer Res. 2000 Dec 1;60(23):6763-70.
PMID 11118064
 
Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance.
Campbell RA, Bhat-Nakshatri P, Patel NM, Constantinidou D, Ali S, Nakshatri H.
J Biol Chem. 2001 Mar 30;276(13):9817-24. Epub 2001 Jan 3.
PMID 11139588
 
Regulation of Akt/PKB activation by tyrosine phosphorylation.
Chen R, Kim O, Yang J, Sato K, Eisenmann KM, McCarthy J, Chen H, Qiu Y.
J Biol Chem. 2001 Aug 24;276(34):31858-62. Epub 2001 Jul 9.
PMID 11445557
 
Nuclear factor-kappaB is constitutively activated in primitive human acute myelogenous leukemia cells.
Guzman ML, Neering SJ, Upchurch D, Grimes B, Howard DS, Rizzieri DA, Luger SM, Jordan CT.
Blood. 2001 Oct 15;98(8):2301-7.
PMID 11588023
 
Biologic sequelae of interleukin-6 induced PI3-K/Akt signaling in multiple myeloma.
Hideshima T, Nakamura N, Chauhan D, Anderson KC.
Oncogene. 2001 Sep 20;20(42):5991-6000.
PMID 11593406
 
HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression.
Laughner E, Taghavi P, Chiles K, Mahon PC, Semenza GL.
Mol Cell Biol. 2001 Jun;21(12):3995-4004.
PMID 11359907
 
Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor.
Lin HK, Yeh S, Kang HY, Chang C.
Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7200-5. Epub 2001 Jun 12.
PMID 11404460
 
A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus.
Mayo LD, Donner DB.
Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11598-603. Epub 2001 Aug 14.
PMID 11504915
 
Akt phosphorylates and regulates the orphan nuclear receptor Nur77.
Pekarsky Y, Hallas C, Palamarchuk A, Koval A, Bullrich F, Hirata Y, Bichi R, Letofsky J, Croce CM.
Proc Natl Acad Sci U S A. 2001 Mar 27;98(7):3690-4.
PMID 11274386
 
p38 Kinase-dependent MAPKAPK-2 activation functions as 3-phosphoinositide-dependent kinase-2 for Akt in human neutrophils.
Rane MJ, Coxon PY, Powell DW, Webster R, Klein JB, Pierce W, Ping P, McLeish KR.
J Biol Chem. 2001 Feb 2;276(5):3517-23. Epub 2000 Oct 20.
PMID 11042204
 
Akt-dependent phosphorylation of p21(Cip1) regulates PCNA binding and proliferation of endothelial cells.
Rossig L, Jadidi AS, Urbich C, Badorff C, Zeiher AM, Dimmeler S.
Mol Cell Biol. 2001 Aug;21(16):5644-57.
PMID 11463845
 
Constitutively active STAT5 variants induce growth and survival of hematopoietic cells through a PI 3-kinase/Akt dependent pathway.
Santos SC, Lacronique V, Bouchaert I, Monni R, Bernard O, Gisselbrecht S, Gouilleux F.
Oncogene. 2001 Apr 19;20(17):2080-90.
PMID 11360192
 
Protein kinase B phosphorylates AHNAK and regulates its subcellular localization.
Sussman J, Stokoe D, Ossina N, Shtivelman E.
J Cell Biol. 2001 Sep 3;154(5):1019-30.
PMID 11535620
 
Expression of cyclin D1 in small cell lymphoma and its clinical implications.
Zhou XH, Zhao T, Zhu MG, Liu ZX, Yang L.
Di Yi Jun Yi Da Xue Xue Bao. 2001;21(12):932-934.
PMID 12426170
 
AKT-1, -2, and -3 are expressed in both normal and tumor tissues of the lung, breast, prostate, and colon.
Zinda MJ, Johnson MA, Paul JD, Horn C, Konicek BW, Lu ZH, Sandusky G, Thomas JE, Neubauer BL, Lai MT, Graff JR.
Clin Cancer Res. 2001 Aug;7(8):2475-9.
PMID 11489829
 
Comprehensive analysis of genomic alterations in gliosarcoma and its two tissue components.
Actor B, Cobbers JM, Buschges R, Wolter M, Knobbe CB, Lichter P, Reifenberger G, Weber RG.
Genes Chromosomes Cancer. 2002 Aug;34(4):416-27.
PMID 12112531
 
Cytokines modulate telomerase activity in a human multiple myeloma cell line.
Akiyama M, Hideshima T, Hayashi T, Tai YT, Mitsiades CS, Mitsiades N, Chauhan D, Richardson P, Munshi NC, Anderson KC.
Cancer Res. 2002 Jul 1;62(13):3876-82.
PMID 12097303
 
The identification of ATP-citrate lyase as a protein kinase B (Akt) substrate in primary adipocytes.
Berwick DC, Hers I, Heesom KJ, Moule SK, Tavare JM.
J Biol Chem. 2002 Sep 13;277(37):33895-900. Epub 2002 Jul 9.
PMID 12107176
 
Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways.
Crackower MA, Oudit GY, Kozieradzki I, Sarao R, Sun H, Sasaki T, Hirsch E, Suzuki A, Shioi T, Irie-Sasaki J, Sah R, Cheng HY, Rybin VO, Lembo G, Fratta L, Oliveira-dos-Santos AJ, Benovic JL, Kahn CR, Izumo S, Steinberg SF, Wymann MP, Backx PH, Penninger JM.
Cell. 2002 Sep 20;110(6):737-49.
PMID 12297047
 
Structure and zymogen activation of caspases.
Donepudi M, Grutter MG.
Biophys Chem. 2002 Dec 10;101-102:145-53. (REVIEW)
PMID 12487996
 
Dysregulation of PTEN and protein kinase B is associated with glioma histology and patient survival.
Ermoian RP, Furniss CS, Lamborn KR, Basila D, Berger MS, Gottschalk AR, Nicholas MK, Stokoe D, Haas-Kogan DA.
Clin Cancer Res. 2002 May;8(5):1100-6.
PMID 12006525
 
Identification of a plasma membrane Raft-associated PKB Ser473 kinase activity that is distinct from ILK and PDK1.
Hill MM, Feng J, Hemmings BA.
Curr Biol. 2002 Jul 23;12(14):1251-5.
PMID 12176337
 
Role of the AKT kinase in expansion of multiple myeloma clones: effects on cytokine-dependent proliferative and survival responses.
Hsu JH, Shi Y, Hu L, Fisher M, Franke TF, Lichtenstein A.
Oncogene. 2002 Feb 21;21(9):1391-400.
PMID 11857082
 
TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling.
Inoki K, Li Y, Zhu T, Wu J, Guan KL.
Nat Cell Biol. 2002 Sep;4(9):648-57.
PMID 12172553
 
Activation of Akt/protein kinase B overcomes a G(2)/m cell cycle checkpoint induced by DNA damage.
Kandel ES, Skeen J, Majewski N, Di Cristofano A, Pandolfi PP, Feliciano CS, Gartel A, Hay N.
Mol Cell Biol. 2002 Nov;22(22):7831-41.
PMID 12391152
 
PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest.
Liang J, Zubovitz J, Petrocelli T, Kotchetkov R, Connor MK, Han K, Lee JH, Ciarallo S, Catzavelos C, Beniston R, Franssen E, Slingerland JM.
Nat Med. 2002 Oct;8(10):1153-60. Epub 2002 Sep 16.
PMID 12244302
 
Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway.
Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC.
Mol Cell. 2002 Jul;10(1):151-62.
PMID 12150915
 
Proliferating or differentiating stimuli act on different lipid-dependent signaling pathways in nuclei of human leukemia cells.
Neri LM, Bortul R, Borgatti P, Tabellini G, Baldini G, Capitani S, Martelli AM.
Mol Biol Cell. 2002 Mar;13(3):947-64.
PMID 11907274
 
The protein kinase B/Akt signalling pathway in human malignancy.
Nicholson KM, Anderson NG.
Cell Signal. 2002 May;14(5):381-95. (REVIEW)
PMID 11882383
 
Akt (protein kinase B) negatively regulates SEK1 by means of protein phosphorylation.
Park HS, Kim MS, Huh SH, Park J, Chung J, Kang SS, Choi EJ.
J Biol Chem. 2002 Jan 25;277(4):2573-8. Epub 2001 Nov 13.
PMID 11707464
 
Role of the phosphatidylinositol 3-kinase/Akt and mTOR/P70S6-kinase pathways in the proliferation and apoptosis in multiple myeloma.
Pene F, Claessens YE, Muller O, Viguie F, Mayeux P, Dreyfus F, Lacombe C, Bouscary D.
Oncogene. 2002 Sep 26;21(43):6587-97.
PMID 12242656
 
Activation of AKT/PKB in breast cancer predicts a worse outcome among endocrine treated patients.
Perez-Tenorio G, Stal O; Southeast Sweden Breast Cancer Group.
Br J Cancer. 2002 Feb 12;86(4):540-5.
PMID 11870534
 
Phosphorylation of glycogen synthase kinase-3beta at serine-9 by phospholipase Cgamma1 through protein kinase C in rat 3Y1 fibroblasts.
Shin SY, Yoon SC, Kim YH, Kim YS, Lee YH.
Exp Mol Med. 2002 Dec 31;34(6):444-50.
PMID 12526086
 
Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27(Kip1) by PKB/Akt-mediated phosphorylation in breast cancer.
Viglietto G, Motti ML, Bruni P, Melillo RM, D'Alessio A, Califano D, Vinci F, Chiappetta G, Tsichlis P, Bellacosa A, Fusco A, Santoro M.
Nat Med. 2002 Oct;8(10):1136-44. Epub 2002 Sep 16.
PMID 12244303
 
Activation of the p53 tumor suppressor protein.
Vousden KH.
Biochim Biophys Acta. 2002 Mar 14;1602(1):47-59. (REVIEW)
PMID 11960694
 
The inducible expression of the tumor suppressor gene PTEN promotes apoptosis and decreases cell size by inhibiting the PI3K/Akt pathway in Jurkat T cells.
Xu Z, Stokoe D, Kane LP, Weiss A.
Cell Growth Differ. 2002 Jul;13(7):285-96.
PMID 12133897
 
Negative regulation of mixed lineage kinase 3 by protein kinase B/AKT leads to cell survival.
Barthwal MK, Sathyanarayana P, Kundu CN, Rana B, Pradeep A, Sharma C, Woodgett JR, Rana A.
J Biol Chem. 2003 Feb 7;278(6):3897-902. Epub 2002 Nov 27.
PMID 12458207
 
Akt phosphorylates the Yes-associated protein, YAP, to induce interaction with 14-3-3 and attenuation of p73-mediated apoptosis.
Basu S, Totty NF, Irwin MS, Sudol M, Downward J.
Mol Cell. 2003 Jan;11(1):11-23.
PMID 12535517
 
Threonine 308 phosphorylated form of Akt translocates to the nucleus of PC12 cells under nerve growth factor stimulation and associates with the nuclear matrix protein nucleolin.
Borgatti P, Martelli AM, Tabellini G, Bellacosa A, Capitani S, Neri LM.
J Cell Physiol. 2003 Jul;196(1):79-88.
PMID 12767043
 
Phosphatase and tensin homologue phosphorylation in the C-terminal regulatory domain is frequently observed in acute myeloid leukaemia and associated with poor clinical outcome.
Cheong JW, Eom JI, Maeng HY, Lee ST, Hahn JS, Ko YW, Min YH.
Br J Haematol. 2003 Aug;122(3):454-6.
PMID 12877673
 
Constitutive phosphorylation of FKHR transcription factor as a prognostic variable in acute myeloid leukemia.
Cheong JW, Eom JI, Maeng HY, Lee ST, Hahn JS, Ko YW, Min YH.
Leuk Res. 2003 Dec;27(12):1159-62.
PMID 12921955
 
SHIP-2 and PTEN are expressed and active in vascular smooth muscle cell nuclei, but only SHIP-2 is associated with nuclear speckles.
Deleris P, Bacqueville D, Gayral S, Carrez L, Salles JP, Perret B, Breton-Douillon M.
J Biol Chem. 2003 Oct 3;278(40):38884-91. Epub 2003 Jul 7.
PMID 12847108
 
PI3K/Akt and apoptosis: size matters.
Franke TF, Hornik CP, Segev L, Shostak GA, Sugimoto C.
Oncogene. 2003 Dec 8;22(56):8983-98. (REVIEW)
PMID 14663477
 
Interaction between Src and a C-terminal proline-rich motif of Akt is required for Akt activation.
Jiang T, Qiu Y.
J Biol Chem. 2003 May 2;278(18):15789-93. Epub 2003 Feb 24.
PMID 12600984
 
Involvement of Akt kinase in the action of STI571 on chronic myelogenous leukemia cells.
Kawauchi K, Ogasawara T, Yasuyama M, Ohkawa S.
Blood Cells Mol Dis. 2003 Jul-Aug;31(1):11-7.
PMID 12850478
 
Genetic alterations and aberrant expression of genes related to the phosphatidyl-inositol-3'-kinase/protein kinase B (Akt) signal transduction pathway in glioblastomas.
Knobbe CB, Reifenberger G.
Brain Pathol. 2003 Oct;13(4):507-18.
PMID 14655756
 
Identification of a proline-rich Akt substrate as a 14-3-3 binding partner.
Kovacina KS, Park GY, Bae SS, Guzzetta AW, Schaefer E, Birnbaum MJ, Roth RA.
J Biol Chem. 2003 Mar 21;278(12):10189-94. Epub 2003 Jan 10.
PMID 12524439
 
Akt/PKB kinase phosphorylates separately Thr212 and Ser214 of tau protein in vitro.
Ksiezak-Reding H, Pyo HK, Feinstein B, Pasinetti GM.
Biochim Biophys Acta. 2003 Nov 20;1639(3):159-68.
PMID 14636947
 
Possible dominant-negative mutation of the SHIP gene in acute myeloid leukemia.
Luo JM, Yoshida H, Komura S, Ohishi N, Pan L, Shigeno K, Hanamura I, Miura K, Iida S, Ueda R, Naoe T, Akao Y, Ohno R, Ohnishi K.
Leukemia. 2003 Jan;17(1):1-8.
PMID 12529653
 
Constitutive phosphorylation of Akt/PKB protein in acute myeloid leukemia: its significance as a prognostic variable.
Min YH, Eom JI, Cheong JW, Maeng HO, Kim JY, Jeung HK, Lee ST, Lee MH, Hahn JS, Ko YW.
Leukemia. 2003 May;17(5):995-7.
PMID 12750723
 
Akt/PKB activation in gastric carcinomas correlates with clinicopathologic variables and prognosis.
Nam SY, Lee HS, Jung GA, Choi J, Cho SJ, Kim MK, Kim WH, Lee BL.
APMIS. 2003 Dec;111(12):1105-13.
PMID 14678019
 
Scansite 2.0: Proteome-wide prediction of cell signaling interactions using short sequence motifs.
Obenauer JC, Cantley LC, Yaffe MB.
Nucleic Acids Res. 2003 Jul 1;31(13):3635-41.
PMID 12824383
 
Constitutive activation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase in B-cell lymphoproliferative disorders.
Ogasawara T, Yasuyama M, Kawauchi K.
Int J Hematol. 2003 May;77(4):364-70.
PMID 12774925
 
Dwarfism, impaired skin development, skeletal muscle atrophy, delayed bone development, and impeded adipogenesis in mice lacking Akt1 and Akt2.
Peng XD, Xu PZ, Chen ML, Hahn-Windgassen A, Skeen J, Jacobs J, Sundararajan D, Chen WS, Crawford SE, Coleman KG, Hay N.
Genes Dev. 2003 Jun 1;17(11):1352-65.
PMID 12782654
 
Insulin-stimulated phosphorylation of a Rab GTPase-activating protein regulates GLUT4 translocation.
Sano H, Kane S, Sano E, Miinea CP, Asara JM, Lane WS, Garner CW, Lienhard GE.
J Biol Chem. 2003 Apr 25;278(17):14599-602. Epub 2003 Mar 11.
PMID 12637568
 
Loss of PTEN expression followed by Akt phosphorylation is a poor prognostic factor for patients with endometrial cancer.
Terakawa N, Kanamori Y, Yoshida S.
Endocr Relat Cancer. 2003 Jun;10(2):203-8.
PMID 12790783
 
Conditional knock-out of integrin-linked kinase demonstrates an essential role in protein kinase B/Akt activation.
Troussard AA, Mawji NM, Ong C, Mui A, St -Arnaud R, Dedhar S.
J Biol Chem. 2003 Jun 20;278(25):22374-8. Epub 2003 Apr 8.
PMID 12686550
 
Survival of acute myeloid leukemia cells requires PI3 kinase activation.
Xu Q, Simpson SE, Scialla TJ, Bagg A, Carroll M.
Blood. 2003 Aug 1;102(3):972-80. Epub 2003 Apr 17.
PMID 12702506
 
Protein kinase B alpha/Akt1 regulates placental development and fetal growth.
Yang ZZ, Tschopp O, Hemmings-Mieszczak M, Feng J, Brodbeck D, Perentes E, Hemmings BA.
J Biol Chem. 2003 Aug 22;278(34):32124-31. Epub 2003 Jun 3.
PMID 12783884
 
A mystery of AHNAK/desmoyokin still goes on.
Amagai M.
J Invest Dermatol. 2004 Oct;123(4):xiv-xv.
PMID 15373799
 
The magnitude of Akt/phosphatidylinositol 3'-kinase proliferating signaling is related to CD45 expression in human myeloma cells.
Descamps G, Pellat-Deceunynck C, Szpak Y, Bataille R, Robillard N, Amiot M.
J Immunol. 2004 Oct 15;173(8):4953-9.
PMID 15470037
 
Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia.
Emamian ES, Hall D, Birnbaum MJ, Karayiorgou M, Gogos JA.
Nat Genet. 2004 Feb;36(2):131-7. Epub 2004 Jan 25.
PMID 14745448
 
Identification of a PKB/Akt hydrophobic motif Ser-473 kinase as DNA-dependent protein kinase.
Feng J, Park J, Cron P, Hess D, Hemmings BA.
J Biol Chem. 2004 Sep 24;279(39):41189-96. Epub 2004 Jul 15.
PMID 15262962
 
In vivo antitumor effects of the mTOR inhibitor CCI-779 against human multiple myeloma cells in a xenograft model.
Frost P, Moatamed F, Hoang B, Shi Y, Gera J, Yan H, Frost P, Gibbons J, Lichtenstein A.
Blood. 2004 Dec 15;104(13):4181-7. Epub 2004 Aug 10.
PMID 15304393
 
Lymphocyte transformation by Pim-2 is dependent on nuclear factor-kappaB activation.
Hammerman PS, Fox CJ, Cinalli RM, Xu A, Wagner JD, Lindsten T, Thompson CB.
Cancer Res. 2004 Nov 15;64(22):8341-8.
PMID 15548703
 
Structure, regulation and function of PKB/AKT--a major therapeutic target.
Hanada M, Feng J, Hemmings BA.
Biochim Biophys Acta. 2004 Mar 11;1697(1-2):3-16. (REVIEW)
PMID 15023346
 
The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins.
Harrington LS, Findlay GM, Gray A, Tolkacheva T, Wigfield S, Rebholz H, Barnett J, Leslie NR, Cheng S, Shepherd PR, Gout I, Downes CP, Lamb RF.
J Cell Biol. 2004 Jul 19;166(2):213-23. Epub 2004 Jul 12.
PMID 15249583
 
The glamour and gloom of glycogen synthase kinase-3.
Jope RS, Johnson GV.
Trends Biochem Sci. 2004 Feb;29(2):95-102. (REVIEW)
PMID 15102436
 
Protein kinase C betaII regulates Akt phosphorylation on Ser-473 in a cell type- and stimulus-specific fashion.
Kawakami Y, Nishimoto H, Kitaura J, Maeda-Yamamoto M, Kato RM, Littman DR, Leitges M, Rawlings DJ, Kawakami T.
J Biol Chem. 2004 Nov 12;279(46):47720-5. Epub 2004 Sep 9.
PMID 15364915
 
Inhibition of Chk1 by activated PKB/Akt.
King FW, Skeen J, Hay N, Shtivelman E.
Cell Cycle. 2004 May;3(5):634-7. Epub 2004 May 31.
PMID 15107605
 
Phosphorylation of Akt (Ser473) is an excellent predictor of poor clinical outcome in prostate cancer.
Kreisberg JI, Malik SN, Prihoda TJ, Bedolla RG, Troyer DA, Kreisberg S, Ghosh PM.
Cancer Res. 2004 Aug 1;64(15):5232-6.
PMID 15289328
 
Phosphorylation of tau at THR212 and SER214 in human neuronal and glial cultures: the role of AKT.
Kyoung Pyo H, Lovati E, Pasinetti GM, Ksiezak-Reding H.
Neuroscience. 2004;127(3):649-58.
PMID 15283964
 
Cytoplasmic mislocalization of p27Kip1 protein is associated with constitutive phosphorylation of Akt or protein kinase B and poor prognosis in acute myelogenous leukemia.
Min YH, Cheong JW, Kim JY, Eom JI, Lee ST, Hahn JS, Ko YW, Lee MH.
Cancer Res. 2004 Aug 1;64(15):5225-31.
PMID 15289327
 
Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies.
Shah OJ, Wang Z, Hunter T.
Curr Biol. 2004 Sep 21;14(18):1650-6.
PMID 15380067
 
JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis.
Steelman LS, Pohnert SC, Shelton JG, Franklin RA, Bertrand FE, McCubrey JA.
Leukemia. 2004 Feb;18(2):189-218. (REVIEW)
PMID 14737178
 
Inhibition of phosphatidylinositol 3'-kinase induces preferentially killing of PTEN-null T leukemias through AKT pathway.
Uddin S, Hussain A, Al-Hussein K, Platanias LC, Bhatia KG.
Biochem Biophys Res Commun. 2004 Jul 30;320(3):932-8.
PMID 15240138
 
WNK1, the kinase mutated in an inherited high-blood-pressure syndrome, is a novel PKB (protein kinase B)/Akt substrate.
Vitari AC, Deak M, Collins BJ, Morrice N, Prescott AR, Phelan A, Humphreys S, Alessi DR.
Biochem J. 2004 Feb 15;378(Pt 1):257-68.
PMID 14611643
 
Prognostic significance of activated Akt expression in pancreatic ductal adenocarcinoma.
Yamamoto S, Tomita Y, Hoshida Y, Morooka T, Nagano H, Dono K, Umeshita K, Sakon M, Ishikawa O, Ohigashi H, Nakamori S, Monden M, Aozasa K.
Clin Cancer Res. 2004 Apr 15;10(8):2846-50.
PMID 15102693
 
Physiological functions of protein kinase B/Akt.
Yang ZZ, Tschopp O, Baudry A, Dummler B, Hynx D, Hemmings BA.
Biochem Soc Trans. 2004 Apr;32(Pt 2):350-4.
PMID 15046607
 
Inhibition of phosphatidylinositol 3-kinase dephosphorylates BAD and promotes apoptosis in myeloid leukemias.
Zhao S, Konopleva M, Cabreira-Hansen M, Xie Z, Hu W, Milella M, Estrov Z, Mills GB, Andreeff M.
Leukemia. 2004 Feb;18(2):267-75.
PMID 14628071
 
Upregulated Akt signaling adjacent to gastric cancers: implications for screening and chemoprevention.
Ang KL, Shi DL, Keong WW, Epstein RJ.
Cancer Lett. 2005 Jul 8;225(1):53-9. Epub 2004 Dec 15.
PMID 15922857
 
Compensatory PI3-kinase/Akt/mTor activation regulates imatinib resistance development.
Burchert A, Wang Y, Cai D, von Bubnoff N, Paschka P, Muller-Brusselbach S, Ottmann OG, Duyster J, Hochhaus A, Neubauer A.
Leukemia. 2005 Oct;19(10):1774-82.
PMID 16136169
 
Prognostic significance of activated Akt expression in melanoma: a clinicopathologic study of 292 cases.
Dai DL, Martinka M, Li G.
J Clin Oncol. 2005 Mar 1;23(7):1473-82.
PMID 15735123
 
Constitutive activation of phosphatidyl-inositide 3 kinase contributes to the survival of Hodgkin's lymphoma cells through a mechanism involving Akt kinase and mTOR.
Dutton A, Reynolds GM, Dawson CW, Young LS, Murray PG.
J Pathol. 2005 Mar;205(4):498-506.
PMID 15714459
 
PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth.
Gao T, Furnari F, Newton AC.
Mol Cell. 2005 Apr 1;18(1):13-24.
PMID 15808505
 
PI3-kinase/Akt is constitutively active in primary acute myeloid leukaemia cells and regulates survival and chemoresistance via NF-kappaB, Mapkinase and p53 pathways.
Grandage VL, Gale RE, Linch DC, Khwaja A.
Leukemia. 2005 Apr;19(4):586-94.
PMID 15703783
 
Proteomic analysis of apoptotic pathways reveals prognostic factors in follicular lymphoma.
Gulmann C, Espina V, Petricoin E 3rd, Longo DL, Santi M, Knutsen T, Raffeld M, Jaffe ES, Liotta LA, Feldman AL.
Clin Cancer Res. 2005 Aug 15;11(16):5847-55.
PMID 16115925
 
Akt activation in renal cell carcinoma: contribution of a decreased PTEN expression and the induction of apoptosis by an Akt inhibitor.
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Written05-2009Daniela Etro, Silvia Missiroli, Francesca Buontempo, Luca Maria Neri, Silvano Capitani
Department of Morphology and Embryology, Human Anatomy Section, Ferrara University, 44100 Ferrara, Italy

Citation

This paper should be referenced as such :
Etro D, Missiroli S, Buontempo F, Neri LM, Capitani S . AKT1 (v-akt murine thymoma viral oncogene homolog 1). Atlas Genet Cytogenet Oncol Haematol. May 2009 .
URL : http://AtlasGeneticsOncology.org/Genes/AKT1ID355ch14q32.html

The various updated versions of this paper are referenced and archived by INIST as such :
http://documents.irevues.inist.fr/bitstream/2042/44725/1/05-2009-AKT1ID355ch14q32.pdf   [ Bibliographic record ]

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