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

2009-05-01   Daniela Etro  , Silvia Missiroli  , Francesca Buontempo  , Luca Maria Neri  , Silvano Capitani  

Department of Morphology, Embryology, Human Anatomy Section, Ferrara University, 44100 Ferrara, Italy

Identity

HGNC
LOCATION
14q32.33
LOCUSID
ALIAS
AKT,PKB,PKB-ALPHA,PRKBA,RAC,RAC-ALPHA
FUSION GENES

DNA/RNA

Atlas Image
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.

Proteins

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).
Atlas Image
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).

Atlas Image
* 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.

Atlas Image

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.
Atlas Image
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.

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 name
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:
-Multiple myeloma
-Acute and chronic leukemia
-Gastro-intestinal stromal tumors
-Bile duct carcinoma
-Renal cell carcinoma
-Lymphoma
Entity name
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 name
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 name
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 name
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 name
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 name
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 name
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 name
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 name
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 name
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 name
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 name
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 (Chng 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 name
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 name
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 name
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 name
Lymphomas
Note
AKT activation has been demonstrated in a variety of B-cell non-Hodgkins 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 Hodgkins 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 name
Various diseases
Note
Alteration of AKT activity is associated with several human diseases, including atherosclerosis, cardiovascular disease, Alzheimer disease, schizophrenia and diabetes.
Entity name
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 name
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 name
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 name
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 name
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).

Article Bibliography

Pubmed IDLast YearTitleAuthors
121125312002Comprehensive analysis of genomic alterations in gliosarcoma and its two tissue components.Actor B et al
120973032002Cytokines modulate telomerase activity in a human multiple myeloma cell line.Akiyama M et al
89786811996Mechanism of activation of protein kinase B by insulin and IGF-1.Alessi DR et al
188462522008Constitutively active Akt1 expression in mouse pancreas requires S6 kinase 1 for insulinoma formation.Alliouachene S et al
105422661999Heregulin induces phosphorylation of BRCA1 through phosphatidylinositol 3-Kinase/AKT in breast cancer cells.Altiok S et al
153737992004A mystery of AHNAK/desmoyokin still goes on.Amagai M et al
93954881997Role of translocation in the activation and function of protein kinase B.Andjelković M et al
159228572005Upregulated Akt signaling adjacent to gastric cancers: implications for screening and chemoprevention.Ang KL et al
182160972008Early phosphatidylinositol 3-kinase/Akt pathway activation limits poliovirus-induced JNK-mediated cell death.Autret A et al
177048062008Phosphorylation by Akt disables the anti-oncogenic activity of YB-1.Bader AG et al
102260251999PDK1 acquires PDK2 activity in the presence of a synthetic peptide derived from the carboxyl terminus of PRK2.Balendran A et al
124582072003Negative regulation of mixed lineage kinase 3 by protein kinase B/AKT leads to cell survival.Barthwal MK et al
125355172003Akt phosphorylates the Yes-associated protein, YAP, to induce interaction with 14-3-3 and attenuation of p73-mediated apoptosis.Basu S et al
84378581993Structure, expression and chromosomal mapping of c-akt: relationship to v-akt and its implications.Bellacosa A et al
121071762002The identification of ATP-citrate lyase as a protein kinase B (Akt) substrate in primary adipocytes.Berwick DC et al
191763692009Inhibition of class I phosphoinositide 3-kinase activity impairs proliferation and triggers apoptosis in acute promyelocytic leukemia without affecting atra-induced differentiation.Billottet C et al
171326282007FOXO3a induces differentiation of Bcr-Abl-transformed cells through transcriptional down-regulation of Id1.Birkenkamp KU et al
114250392000Granulocyte/macrophage colony-stimulating factor plays an essential role in oxidized low density lipoprotein-induced macrophage proliferation.Biwa T et al
187982582008An activating mutation in AKT1 in human prostate cancer.Boormans JL et al
127670432003Threonine 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 et al
173862672007PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms.Brognard J et al
161361692005Compensatory PI3-kinase/Akt/mTor activation regulates imatinib resistance development.Burchert A et al
111395882001Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance.Campbell RA et al
176114972007A transforming mutation in the pleckstrin homology domain of AKT1 in cancer.Carpten JD et al
192731082009Genetics, cellular biology and tumor microenvironment of melanoma.Ch'ng S et al
175726612007Akt phosphorylation of zyxin mediates its interaction with acinus-S and prevents acinus-triggered chromatin condensation.Chan CB et al
187014942008Down-regulation of phospho-Akt is a major molecular determinant of bortezomib-induced apoptosis in hepatocellular carcinoma cells.Chen KF et al
114455572001Regulation of Akt/PKB activation by tyrosine phosphorylation.Chen R et al
129219552003Constitutive phosphorylation of FKHR transcription factor as a prognostic variable in acute myeloid leukemia.Cheong JW et al
17187481991Molecular cloning and characterisation of a novel putative protein-serine kinase related to the cAMP-dependent and protein kinase C families.Coffer PJ et al
182048292008Isoform-specific defects of insulin stimulation of Akt/protein kinase B (PKB) in skeletal muscle cells from type 2 diabetic patients.Cozzone D et al
122970472002Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways.Crackower MA et al
192181472009[Akt enzyme: new therapeutic target in cancer and diabetes?].Cseh A et al
183910712008The eIF4E RNA regulon promotes the Akt signaling pathway.Culjkovic B et al
157351232005Prognostic significance of activated Akt expression in melanoma: a clinicopathologic study of 292 cases.Dai DL et al
183398992008Distinct functional significance of Akt and mTOR constitutive activation in mantle cell lymphoma.Dal Col J et al
86436911996The 145-kDa protein induced to associate with Shc by multiple cytokines is an inositol tetraphosphate and phosphatidylinositol 3,4,5-triphosphate 5-phosphatase.Damen JE et al
93462401997Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery.Datta SR et al
97367151998Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase.Delcommenne M et al
128471082003SHIP-2 and PTEN are expressed and active in vascular smooth muscle cell nuclei, but only SHIP-2 is associated with nuclear speckles.Déléris P et al
154700372004The magnitude of Akt/phosphatidylinositol 3'-kinase proliferating signaling is related to CD45 expression in human myeloma cells.Descamps G et al
98325031998Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization.Diehl JA et al
124879962002Structure and zymogen activation of caspases.Donepudi M et al
105598901999How BAD phosphorylation is good for survival.Downward J et al
98299641998CREB is a regulatory target for the protein kinase Akt/PKB.Du K et al
157144592005Constitutive 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 et al
147454482004Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia.Emamian ES et al
120065252002Dysregulation of PTEN and protein kinase B is associated with glioma histology and patient survival.Ermoian RP et al
152629622004Identification of a PKB/Akt hydrophobic motif Ser-473 kinase as DNA-dependent protein kinase.Feng J et al
146634772003PI3K/Akt and apoptosis: size matters.Franke TF et al
153043932004In vivo antitumor effects of the mTOR inhibitor CCI-779 against human multiple myeloma cells in a xenograft model.Frost P et al
191588292009The level of AKT phosphorylation on threonine 308 but not on serine 473 is associated with high-risk cytogenetics and predicts poor overall survival in acute myeloid leukaemia.Gallay N et al
158085052005PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth.Gao T et al
157037832005PI3-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 et al
187980612008Over-expression of COX-2 induces human ovarian cancer cells (CAOV-3) viability, migration and proliferation in association with PI3-k/Akt activation.Gu P et al
108693592000Negative regulation of the serine/threonine kinase B-Raf by Akt.Guan KL et al
161159252005Proteomic analysis of apoptotic pathways reveals prognostic factors in follicular lymphoma.Gulmann C et al
115880232001Nuclear factor-kappaB is constitutively activated in primitive human acute myelogenous leukemia cells.Guzman ML et al
155487032004Lymphocyte transformation by Pim-2 is dependent on nuclear factor-kappaB activation.Hammerman PS et al
185070422008Characterization of Akt overexpression in MiaPaCa-2 cells: prohibitin is an Akt substrate both in vitro and in cells.Han EK et al
150233462004Structure, regulation and function of PKB/AKT--a major therapeutic target.Hanada M et al
158514052005Akt activation in renal cell carcinoma: contribution of a decreased PTEN expression and the induction of apoptosis by an Akt inhibitor.Hara S et al
152495832004The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins.Harrington LS et al
115934062001Biologic sequelae of interleukin-6 induced PI3-K/Akt signaling in multiple myeloma.Hideshima T et al
121763372002Identification of a plasma membrane Raft-associated PKB Ser473 kinase activity that is distinct from ILK and PDK1.Hill MM et al
118570822002Role of the AKT kinase in expansion of multiple myeloma clones: effects on cytokine-dependent proliferative and survival responses.Hsu JH et al
161778232005Akt phosphorylates acinus and inhibits its proteolytic cleavage, preventing chromatin condensation.Hu Y et al
161744432005Expression of proline-rich Akt-substrate PRAS40 in cell survival pathway and carcinogenesis.Huang B et al
193226692009Sendai viral vector mediated angiopoietin-1 gene transfer for experimental ischemic limb disease.Huang J et al
171060602007Ghrelin has novel vascular actions that mimic PI 3-kinase-dependent actions of insulin to stimulate production of NO from endothelial cells.Iantorno M et al
121725532002TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling.Inoki K et al
192160692009A novel signaling network as a critical rheostat for the biology and maintenance of the normal stem cell and the cancer-initiating cell.Ito K et al
110855462000Remarkable tolerance of tumor cells to nutrient deprivation: possible new biochemical target for cancer therapy.Izuishi K et al
126009842003Interaction between Src and a C-terminal proline-rich motif of Akt is required for Akt activation.Jiang T et al
151024362004The glamour and gloom of glycogen synthase kinase-3.Jope RS et al
123911522002Activation of Akt/protein kinase B overcomes a G(2)/m cell cycle checkpoint induced by DNA damage.Kandel ES et al
185709202008O-GlcNAc modulation at Akt1 Ser473 correlates with apoptosis of murine pancreatic beta cells.Kang ES et al
102240601999Akt protein kinase enhances human telomerase activity through phosphorylation of telomerase reverse transcriptase subunit.Kang SS et al
172305132007Inhibition of heat shock protein-90 modulates multiple functions required for survival of human T-cell leukemia virus type I-infected T-cell lines and adult T-cell leukemia cells.Kawakami H et al
153649152004Protein kinase C betaII regulates Akt phosphorylation on Ser-473 in a cell type- and stimulus-specific fashion.Kawakami Y et al
128504782003Involvement of Akt kinase in the action of STI571 on chronic myelogenous leukemia cells.Kawauchi K et al
157816102005ABL oncogenes and phosphoinositide 3-kinase: mechanism of activation and downstream effectors.Kharas MG et al
160025272005AKT activation promotes metastasis in a mouse model of follicular thyroid carcinoma.Kim CS et al
187796572008Lysophosphatidic acid induces cell migration through the selective activation of Akt1.Kim EK et al
183920552008Mutational analysis of oncogenic AKT E17K mutation in common solid cancers and acute leukaemias.Kim MS et al
151076052004Inhibition of Chk1 by activated PKB/Akt.King FW et al
18623421991Crystal structure of the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase.Knighton DR et al
146557562003Genetic alterations and aberrant expression of genes related to the phosphatidyl-inositol-3'-kinase/protein kinase B (Akt) signal transduction pathway in glioblastomas.Knobbe CB et al
104908481999Cloning and characterization of a nuclear S6 kinase, S6 kinase-related kinase (SRK); a novel nuclear target of Akt.Koh H et al
89401451996Expression of a constitutively active Akt Ser/Thr kinase in 3T3-L1 adipocytes stimulates glucose uptake and glucose transporter 4 translocation.Kohn AD et al
167632102006Simultaneous activation of multiple signal transduction pathways confers poor prognosis in acute myelogenous leukemia.Kornblau SM et al
125244392003Identification of a proline-rich Akt substrate as a 14-3-3 binding partner.Kovacina KS et al
152893282004Phosphorylation of Akt (Ser473) is an excellent predictor of poor clinical outcome in prostate cancer.Kreisberg JI et al
146369472003Akt/PKB kinase phosphorylates separately Thr212 and Ser214 of tau protein in vitro.Ksiezak-Reding H et al
162882962005AKT crystal structure and AKT-specific inhibitors.Kumar CC et al
152839642004Phosphorylation of tau at THR212 and SER214 in human neuronal and glial cultures: the role of AKT.Kyoung Pyo H et al
113599072001HER2 (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 et al
158146282005Nuclear factor-kappaB activation correlates with better prognosis and Akt activation in human gastric cancer.Lee BL et al
89786851996The Drosophila phosphoinositide 3-kinase Dp110 promotes cell growth.Leevers SJ et al
165494262006Autophosphorylation of Akt at threonine 72 and serine 246. A potential mechanism of regulation of Akt kinase activity.Li X et al
175543392007Akt/PKB regulates hepatic metabolism by directly inhibiting PGC-1alpha transcription coactivator.Li X et al
122443022002PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest.Liang J et al
114044602001Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor.Lin HK et al
184927512008Highly prevalent genetic alterations in receptor tyrosine kinases and phosphatidylinositol 3-kinase/akt and mitogen-activated protein kinase pathways in anaplastic and follicular thyroid cancers.Liu Z et al
183919782008DNA amplification is a ubiquitous mechanism of oncogene activation in lung and other cancers.Lockwood WW et al
179285282008The Akt/Mcl-1 pathway plays a prominent role in mediating antiapoptotic signals downstream of the B-cell receptor in chronic lymphocytic leukemia B cells.Longo PG et al
125296532003Possible dominant-negative mutation of the SHIP gene in acute myeloid leukemia.Luo JM et al
106375131999Integrin-linked kinase regulates phosphorylation of serine 473 of protein kinase B by an indirect mechanism.Lynch DK et al
178911742008CD133+ HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway.Ma S et al
95936641998The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate.Maehama T et al
182565402008Activating E17K mutation in the gene encoding the protein kinase AKT1 in a subset of squamous cell carcinoma of the lung.Malanga D et al
158707082005The Akt inhibitor KP372-1 suppresses Akt activity and cell proliferation and induces apoptosis in thyroid cancer cells.Mandal M et al
176047172007AKT/PKB signaling: navigating downstream.Manning BD et al
168851482006Role of insulin, adipocyte hormones, and nutrient-sensing pathways in regulating fuel metabolism and energy homeostasis: a nutritional perspective of diabetes, obesity, and cancer.Marshall S et al
176919432007Targeting the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin module for acute myelogenous leukemia therapy: from bench to bedside.Martelli AM et al
104911921999Molecular cloning, expression and characterization of the human serine/threonine kinase Akt-3.Masure S et al
115049152001A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus.Mayo LD et al
158433772005Phosphorylation of human p53 at serine 46 determines promoter selection and whether apoptosis is attenuated or amplified.Mayo LD et al
93305841997Novel pharmacological approaches to the prevention and treatment of non-insulin-dependent diabetes mellitus.Meier CA et al
168397452006Role of PI3K and AKT specific isoforms in ovarian cancer cell migration, invasion and proliferation through the p70S6K1 pathway.Meng Q et al
158379482005Phosphorylation of GATA2 by Akt increases adipose tissue differentiation and reduces adipose tissue-related inflammation: a novel pathway linking obesity to atherosclerosis.Menghini R et al
184614482008Inhibition of Wnt and PI3K signaling modulates GSK-3beta activity and induces morphological changes in cortical neurons: role of tau phosphorylation.Mercado-Gómez O et al
152893272004Cytoplasmic mislocalization of p27Kip1 protein is associated with constitutive phosphorylation of Akt or protein kinase B and poor prognosis in acute myelogenous leukemia.Min YH et al
127507232003Constitutive phosphorylation of Akt/PKB protein in acute myeloid leukemia: its significance as a prognostic variable.Min YH et al
179605832007BCL-2 functions as an activator of the AKT signaling pathway in pancreatic cancer.Mortenson MM et al
155930872005Akt phosphorylation is a risk factor for early disease recurrence and poor prognosis in hepatocellular carcinoma.Nakanishi K et al
146780192003Akt/PKB activation in gastric carcinomas correlates with clinicopathologic variables and prognosis.Nam SY et al
171304642006Insulin-mediated phosphorylation of the proline-rich Akt substrate PRAS40 is impaired in insulin target tissues of high-fat diet-fed rats.Nascimento EB et al
119072742002Proliferating or differentiating stimuli act on different lipid-dependent signaling pathways in nuclei of human leukemia cells.Neri LM et al
118823832002The protein kinase B/Akt signalling pathway in human malignancy.Nicholson KM et al
128243832003Scansite 2.0: Proteome-wide prediction of cell signaling interactions using short sequence motifs.Obenauer JC et al
127749252003Constitutive activation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase in B-cell lymphoproliferative disorders.Ogasawara T et al
172399302007Cytoplasmic localization of p27 (cyclin-dependent kinase inhibitor 1B/KIP1) in colorectal cancer: inverse correlations with nuclear p27 loss, microsatellite instability, and CpG island methylator phenotype.Ogino S et al
185622792008Akt phosphorylation and nuclear phosphoinositide association mediate mRNA export and cell proliferation activities by ALY.Okada M et al
159005962005Akt phosphorylation associates with LOH of PTEN and leads to chemoresistance for gastric cancer.Oki E et al
104857101999NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase.Ozes ON et al
159302672005Akt phosphorylates Tal1 oncoprotein and inhibits its repressor activity.Palamarchuk A et al
178738822007Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia.Palomero T et al
117074642002Akt (protein kinase B) negatively regulates SEK1 by means of protein phosphorylation.Park HS et al
112743862001Akt phosphorylates and regulates the orphan nuclear receptor Nur77.Pekarsky Y et al
122426562002Role of the phosphatidylinositol 3-kinase/Akt and mTOR/P70S6-kinase pathways in the proliferation and apoptosis in multiple myeloma.Pene F et al
127826542003Dwarfism, impaired skin development, skeletal muscle atrophy, delayed bone development, and impeded adipogenesis in mice lacking Akt1 and Akt2.Peng XD et al
118705342002Activation of AKT/PKB in breast cancer predicts a worse outcome among endocrine treated patients.Pérez-Tenorio G et al
182881292008Lack of the leukocyte-associated Ig-like receptor-1 expression in high-risk chronic lymphocytic leukaemia results in the absence of a negative signal regulating kinase activation and cell division.Poggi A et al
191391182009Synergy between phosphatidylinositol 3-kinase/Akt pathway and Bcl-xL in the control of apoptosis in adenocarcinoma cells of the lung.Qian J et al
110422042001p38 Kinase-dependent MAPKAPK-2 activation functions as 3-phosphoinositide-dependent kinase-2 for Akt in human neutrophils.Rane MJ et al
153748802005Inhibition of Akt increases p27Kip1 levels and induces cell cycle arrest in anaplastic large cell lymphoma.Rassidakis GZ et al
159181492005Hepatocellular carcinoma: molecular pathways and new therapeutic targets.Roberts LR et al
104857111999NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling.Romashkova JA et al
114638452001Akt-dependent phosphorylation of p21(Cip1) regulates PCNA binding and proliferation of endothelial cells.Rössig L et al
166451632006Constitutive activation of Akt contributes to the pathogenesis and survival of mantle cell lymphoma.Rudelius M et al
158963132005Akt1 contains a functional leucine-rich nuclear export sequence.Saji M et al
126375682003Insulin-stimulated phosphorylation of a Rab GTPase-activating protein regulates GLUT4 translocation.Sano H et al
113601922001Constitutively active STAT5 variants induce growth and survival of hematopoietic cells through a PI 3-kinase/Akt dependent pathway.Santos SC et al
157184702005Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex.Sarbassov DD et al
164845922006Phosphatidylinositol-3-phosphate kinase pathway activation protects leukemic large granular lymphocytes from undergoing homeostatic apoptosis.Schade AE et al
191877712009CXCL10 impairs beta cell function and viability in diabetes through TLR4 signaling.Schulthess FT et al
160267662005Further evidence for association of variants in the AKT1 gene with schizophrenia in a sample of European sib-pair families.Schwab SG et al
153800672004Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies.Shah OJ et al
125260862002Phosphorylation of glycogen synthase kinase-3beta at serine-9 by phospholipase Cgamma1 through protein kinase C in rat 3Y1 fibroblasts.Shin SY et al
93213941997Transformation of hematopoietic cells by BCR/ABL requires activation of a PI-3k/Akt-dependent pathway.Skorski T et al
30375311987Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: amplification of AKT1 in a primary human gastric adenocarcinoma.Staal SP et al
158019082005IGF-I stimulation of proteoglycan synthesis by chondrocytes requires activation of the PI 3-kinase pathway but not ERK MAPK.Starkman BG et al
147371782004JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis.Steelman LS et al
115356202001Protein kinase B phosphorylates AHNAK and regulates its subcellular localization.Sussman J et al
162783802005X-Linked inhibitor of apoptosis protein expression level in colorectal cancer is regulated by hepatocyte growth factor/C-met pathway via Akt signaling.Takeuchi H et al
174262582007Constitutive phosphoinositide 3-kinase/Akt activation represents a favorable prognostic factor in de novo acute myelogenous leukemia patients.Tamburini J et al
178911372007Akt phosphorylation regulates the tumour-suppressor merlin through ubiquitination and degradation.Tang X et al
127907832003Loss of PTEN expression followed by Akt phosphorylation is a poor prognostic factor for patients with endometrial cancer.Terakawa N et al
173177262007FAK association with multiple signal proteins mediates pressure-induced colon cancer cell adhesion via a Src-dependent PI3K/Akt pathway.Thamilselvan V et al
110578912000Cellular signaling: pivoting around PDK-1.Toker A et al
126865502003Conditional knock-out of integrin-linked kinase demonstrates an essential role in protein kinase B/Akt activation.Troussard AA et al
163306712006Evaluation of two phosphorylation sites improves the prognostic significance of Akt activation in non-small-cell lung cancer tumors.Tsurutani J et al
111180642000The phosphatidylinositol 3-kinase/AKT kinase pathway in multiple myeloma plasma cells: roles in cytokine-dependent survival and proliferative responses.Tu Y et al
169463032006Role of phosphatidylinositol 3'-kinase/AKT pathway in diffuse large B-cell lymphoma survival.Uddin S et al
175604682007Goiter and other iodine deficiency disorders: a systematic review of epidemiological studies to deconstruct the complex web.Van Der Haar F et al
177218852008Overexpression of Akt1 upregulates glycogen synthase activity and phosphorylation of mTOR in IRS-1 knockdown HepG2 cells.Varma S et al
168186312006Activation of mammalian target of rapamycin signaling pathway contributes to tumor cell survival in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma.Vega F et al
105876461999Cell-autonomous regulation of cell and organ growth in Drosophila by Akt/PKB.Verdu J et al
122443032002Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27(Kip1) by PKB/Akt-mediated phosphorylation in breast cancer.Viglietto G et al
146116432004WNK1, the kinase mutated in an inherited high-blood-pressure syndrome, is a novel PKB (protein kinase B)/Akt substrate.Vitari AC et al
119606942002Activation of the p53 tumor suppressor protein.Vousden KH et al
95124931998Activation of protein kinase B beta and gamma isoforms by insulin in vivo and by 3-phosphoinositide-dependent protein kinase-1 in vitro: comparison with protein kinase B alpha.Walker KS et al
192934292009Obesity increases vascular senescence and susceptibility to ischemic injury through chronic activation of Akt and mTOR.Wang CY et al
190074362008The UPS in diabetes and obesity.Wing SS et al
127025062003Survival of acute myeloid leukemia cells requires PI3 kinase activation.Xu Q et al
121338972002The 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 et al
169565802006Akt phosphorylation is essential for nuclear translocation and retention in NGF-stimulated PC12 cells.Xuan Nguyen TL et al
151026932004Prognostic significance of activated Akt expression in pancreatic ductal adenocarcinoma.Yamamoto S et al
150466072004Physiological functions of protein kinase B/Akt.Yang ZZ et al
192584132009Akt/protein kinase b and glycogen synthase kinase-3beta signaling pathway regulates cell migration through the NFAT1 transcription factor.Yoeli-Lerner M et al
89295311996Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L).Zha J et al
146280712004Inhibition of phosphatidylinositol 3-kinase dephosphorylates BAD and promotes apoptosis in myeloid leukemias.Zhao S et al
182151342008Akt substrate TBC1D1 regulates GLUT1 expression through the mTOR pathway in 3T3-L1 adipocytes.Zhou QL et al
124261702001Expression of cyclin D1 in small cell lymphoma and its clinical implications.Zhou XH et al
174001902007Real-time imaging nuclear translocation of Akt1 in HCC cells.Zhu L et al
105767421999Phosphorylation and regulation of Raf by Akt (protein kinase B).Zimmermann S et al
114898292001AKT-1, -2, and -3 are expressed in both normal and tumor tissues of the lung, breast, prostate, and colon.Zinda MJ et al
93811781997Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt.del Peso L et al

Other Information

Locus ID:

NCBI: 207
MIM: 164730
HGNC: 391
Ensembl: ENSG00000142208

Variants:

dbSNP: 207
ClinVar: 207
TCGA: ENSG00000142208
COSMIC: AKT1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000142208ENST00000349310P31749
ENSG00000142208ENST00000349310B0LPE5
ENSG00000142208ENST00000402615P31749
ENSG00000142208ENST00000402615B0LPE5
ENSG00000142208ENST00000407796P31749
ENSG00000142208ENST00000407796B0LPE5
ENSG00000142208ENST00000554192G3V2I6
ENSG00000142208ENST00000554581P31749
ENSG00000142208ENST00000554581B0LPE5
ENSG00000142208ENST00000554585A0A087WY56
ENSG00000142208ENST00000554848P31749
ENSG00000142208ENST00000554848B0LPE5
ENSG00000142208ENST00000555458G3V3X1
ENSG00000142208ENST00000555528P31749
ENSG00000142208ENST00000555528B0LPE5
ENSG00000142208ENST00000555926G3V4I6
ENSG00000142208ENST00000649815P31749
ENSG00000142208ENST00000649815B0LPE5

Expression (GTEx)

0
10
20
30
40
50
60
70
80
90

Pathways

PathwaySourceExternal ID
MAPK signaling pathwayKEGGko04010
ErbB signaling pathwayKEGGko04012
Autophagy - animalKEGGko04140
mTOR signaling pathwayKEGGko04150
ApoptosisKEGGko04210
VEGF signaling pathwayKEGGko04370
Focal adhesionKEGGko04510
Toll-like receptor signaling pathwayKEGGko04620
Jak-STAT signaling pathwayKEGGko04630
T cell receptor signaling pathwayKEGGko04660
B cell receptor signaling pathwayKEGGko04662
Fc epsilon RI signaling pathwayKEGGko04664
Insulin signaling pathwayKEGGko04910
Progesterone-mediated oocyte maturationKEGGko04914
Adipocytokine signaling pathwayKEGGko04920
Colorectal cancerKEGGko05210
Renal cell carcinomaKEGGko05211
Pancreatic cancerKEGGko05212
Endometrial cancerKEGGko05213
GliomaKEGGko05214
Prostate cancerKEGGko05215
MelanomaKEGGko05218
Chronic myeloid leukemiaKEGGko05220
Acute myeloid leukemiaKEGGko05221
Small cell lung cancerKEGGko05222
Non-small cell lung cancerKEGGko05223
MAPK signaling pathwayKEGGhsa04010
ErbB signaling pathwayKEGGhsa04012
Autophagy - animalKEGGhsa04140
mTOR signaling pathwayKEGGhsa04150
ApoptosisKEGGhsa04210
VEGF signaling pathwayKEGGhsa04370
Focal adhesionKEGGhsa04510
Toll-like receptor signaling pathwayKEGGhsa04620
Jak-STAT signaling pathwayKEGGhsa04630
T cell receptor signaling pathwayKEGGhsa04660
B cell receptor signaling pathwayKEGGhsa04662
Fc epsilon RI signaling pathwayKEGGhsa04664
Insulin signaling pathwayKEGGhsa04910
Adipocytokine signaling pathwayKEGGhsa04920
Pathways in cancerKEGGhsa05200
Colorectal cancerKEGGhsa05210
Renal cell carcinomaKEGGhsa05211
Pancreatic cancerKEGGhsa05212
Endometrial cancerKEGGhsa05213
GliomaKEGGhsa05214
Prostate cancerKEGGhsa05215
MelanomaKEGGhsa05218
Chronic myeloid leukemiaKEGGhsa05220
Acute myeloid leukemiaKEGGhsa05221
Small cell lung cancerKEGGhsa05222
Non-small cell lung cancerKEGGhsa05223
Chemokine signaling pathwayKEGGko04062
Chemokine signaling pathwayKEGGhsa04062
Neurotrophin signaling pathwayKEGGko04722
Neurotrophin signaling pathwayKEGGhsa04722
Fc gamma R-mediated phagocytosisKEGGko04666
Fc gamma R-mediated phagocytosisKEGGhsa04666
Progesterone-mediated oocyte maturationKEGGhsa04914
Chagas disease (American trypanosomiasis)KEGGko05142
Chagas disease (American trypanosomiasis)KEGGhsa05142
ToxoplasmosisKEGGko05145
ToxoplasmosisKEGGhsa05145
Carbohydrate digestion and absorptionKEGGko04973
Carbohydrate digestion and absorptionKEGGhsa04973
Hepatitis CKEGGko05160
Hepatitis CKEGGhsa05160
Osteoclast differentiationKEGGko04380
Osteoclast differentiationKEGGhsa04380
MeaslesKEGGko05162
MeaslesKEGGhsa05162
TuberculosisKEGGko05152
TuberculosisKEGGhsa05152
Influenza AKEGGko05164
Influenza AKEGGhsa05164
Cholinergic synapseKEGGhsa04725
HTLV-I infectionKEGGko05166
HTLV-I infectionKEGGhsa05166
Dopaminergic synapseKEGGko04728
Dopaminergic synapseKEGGhsa04728
Epstein-Barr virus infectionKEGGhsa05169
Epstein-Barr virus infectionKEGGko05169
PI3K-Akt signaling pathwayKEGGhsa04151
PI3K-Akt signaling pathwayKEGGko04151
Hepatitis BKEGGhsa05161
HIF-1 signaling pathwayKEGGhsa04066
Proteoglycans in cancerKEGGhsa05205
Proteoglycans in cancerKEGGko05205
Estrogen signaling pathwayKEGGhsa04915
Estrogen signaling pathwayKEGGko04915
TNF signaling pathwayKEGGhsa04668
TNF signaling pathwayKEGGko04668
Prolactin signaling pathwayKEGGhsa04917
Prolactin signaling pathwayKEGGko04917
Non-alcoholic fatty liver disease (NAFLD)KEGGhsa04932
Non-alcoholic fatty liver disease (NAFLD)KEGGko04932
Ras signaling pathwayKEGGhsa04014
Rap1 signaling pathwayKEGGhsa04015
Rap1 signaling pathwayKEGGko04015
Adrenergic signaling in cardiomyocytesKEGGhsa04261
Adrenergic signaling in cardiomyocytesKEGGko04261
FoxO signaling pathwayKEGGhsa04068
Thyroid hormone signaling pathwayKEGGhsa04919
Platelet activationKEGGhsa04611
cGMP-PKG signaling pathwayKEGGhsa04022
cGMP-PKG signaling pathwayKEGGko04022
AMPK signaling pathwayKEGGhsa04152
AMPK signaling pathwayKEGGko04152
cAMP signaling pathwayKEGGhsa04024
cAMP signaling pathwayKEGGko04024
Signaling pathways regulating pluripotency of stem cellsKEGGhsa04550
Signaling pathways regulating pluripotency of stem cellsKEGGko04550
Central carbon metabolism in cancerKEGGhsa05230
Choline metabolism in cancerKEGGhsa05231
Central carbon metabolism in cancerKEGGko05230
Choline metabolism in cancerKEGGko05231
PI3K-Akt signalingKEGGhsa_M00676
PI3K-Akt signalingKEGGM00676
Sphingolipid signaling pathwayKEGGhsa04071
Glucagon signaling pathwayKEGGhsa04922
Sphingolipid signaling pathwayKEGGko04071
Glucagon signaling pathwayKEGGko04922
Regulation of lipolysis in adipocytesKEGGhsa04923
DiseaseREACTOMER-HSA-1643685
Diseases of signal transductionREACTOMER-HSA-5663202
PI3K/AKT Signaling in CancerREACTOMER-HSA-2219528
Constitutive Signaling by AKT1 E17K in CancerREACTOMER-HSA-5674400
Immune SystemREACTOMER-HSA-168256
Adaptive Immune SystemREACTOMER-HSA-1280218
Costimulation by the CD28 familyREACTOMER-HSA-388841
CD28 co-stimulationREACTOMER-HSA-389356
CD28 dependent PI3K/Akt signalingREACTOMER-HSA-389357
CTLA4 inhibitory signalingREACTOMER-HSA-389513
Signaling by the B Cell Receptor (BCR)REACTOMER-HSA-983705
Downstream signaling events of B Cell Receptor (BCR)REACTOMER-HSA-1168372
PIP3 activates AKT signalingREACTOMER-HSA-1257604
AKT phosphorylates targets in the cytosolREACTOMER-HSA-198323
AKT phosphorylates targets in the nucleusREACTOMER-HSA-198693
Negative regulation of the PI3K/AKT networkREACTOMER-HSA-199418
Innate Immune SystemREACTOMER-HSA-168249
DAP12 interactionsREACTOMER-HSA-2172127
DAP12 signalingREACTOMER-HSA-2424491
Fc epsilon receptor (FCERI) signalingREACTOMER-HSA-2454202
Role of LAT2/NTAL/LAB on calcium mobilizationREACTOMER-HSA-2730905
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147
HemostasisREACTOMER-HSA-109582
Platelet activation, signaling and aggregationREACTOMER-HSA-76002
GPVI-mediated activation cascadeREACTOMER-HSA-114604
Platelet Aggregation (Plug Formation)REACTOMER-HSA-76009
Integrin alphaIIb beta3 signalingREACTOMER-HSA-354192
Signal TransductionREACTOMER-HSA-162582
Signaling by EGFRREACTOMER-HSA-177929
GAB1 signalosomeREACTOMER-HSA-180292
Signaling by Insulin receptorREACTOMER-HSA-74752
Insulin receptor signalling cascadeREACTOMER-HSA-74751
IRS-mediated signallingREACTOMER-HSA-112399
PI3K CascadeREACTOMER-HSA-109704
PKB-mediated eventsREACTOMER-HSA-109703
mTOR signallingREACTOMER-HSA-165159
Signalling by NGFREACTOMER-HSA-166520
NGF signalling via TRKA from the plasma membraneREACTOMER-HSA-187037
PI3K/AKT activationREACTOMER-HSA-198203
Signaling by PDGFREACTOMER-HSA-186797
Downstream signal transductionREACTOMER-HSA-186763
Signaling by VEGFREACTOMER-HSA-194138
VEGFA-VEGFR2 PathwayREACTOMER-HSA-4420097
VEGFR2 mediated vascular permeabilityREACTOMER-HSA-5218920
Signaling by SCF-KITREACTOMER-HSA-1433557
Signaling by ERBB2REACTOMER-HSA-1227986
Downregulation of ERBB2:ERBB3 signalingREACTOMER-HSA-1358803
Signaling by GPCRREACTOMER-HSA-372790
GPCR downstream signalingREACTOMER-HSA-388396
G-protein beta:gamma signallingREACTOMER-HSA-397795
G beta:gamma signalling through PI3KgammaREACTOMER-HSA-392451
Signaling by WntREACTOMER-HSA-195721
TCF dependent signaling in response to WNTREACTOMER-HSA-201681
Deactivation of the beta-catenin transactivating complexREACTOMER-HSA-3769402
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)REACTOMER-HSA-2404192
IGF1R signaling cascadeREACTOMER-HSA-2428924
IRS-related events triggered by IGF1RREACTOMER-HSA-2428928
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
Transcriptional Regulation by TP53REACTOMER-HSA-3700989
TP53 Regulates Metabolic GenesREACTOMER-HSA-5628897
Regulation of mRNA stability by proteins that bind AU-rich elementsREACTOMER-HSA-450531
Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNAREACTOMER-HSA-450385
KSRP (KHSRP) binds and destabilizes mRNAREACTOMER-HSA-450604
Cell CycleREACTOMER-HSA-1640170
Cell Cycle, MitoticREACTOMER-HSA-69278
Mitotic G1-G1/S phasesREACTOMER-HSA-453279
G1/S TransitionREACTOMER-HSA-69206
Cyclin E associated events during G1/S transitionREACTOMER-HSA-69202
Vesicle-mediated transportREACTOMER-HSA-5653656
Membrane TraffickingREACTOMER-HSA-199991
Translocation of GLUT4 to the plasma membraneREACTOMER-HSA-1445148
MetabolismREACTOMER-HSA-1430728
Metabolism of nitric oxideREACTOMER-HSA-202131
eNOS activation and regulationREACTOMER-HSA-203765
eNOS activationREACTOMER-HSA-203615
Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulationREACTOMER-HSA-1474151
Programmed Cell DeathREACTOMER-HSA-5357801
ApoptosisREACTOMER-HSA-109581
Intrinsic Pathway for ApoptosisREACTOMER-HSA-109606
Activation of BH3-only proteinsREACTOMER-HSA-114452
Activation of BAD and translocation to mitochondriaREACTOMER-HSA-111447
Developmental BiologyREACTOMER-HSA-1266738
Regulation of beta-cell developmentREACTOMER-HSA-186712
Regulation of gene expression in beta cellsREACTOMER-HSA-210745
AKT-mediated inactivation of FOXO1AREACTOMER-HSA-211163
Insulin resistanceKEGGhsa04931
Phospholipase D signaling pathwayKEGGko04072
Phospholipase D signaling pathwayKEGGhsa04072
AGE-RAGE signaling pathway in diabetic complicationsKEGGko04933
AGE-RAGE signaling pathway in diabetic complicationsKEGGhsa04933
Longevity regulating pathwayKEGGhsa04211
Longevity regulating pathway - multiple speciesKEGGko04213
Longevity regulating pathway - multiple speciesKEGGhsa04213
PI5P, PP2A and IER3 Regulate PI3K/AKT SignalingREACTOMER-HSA-6811558
Signaling by PTK6REACTOMER-HSA-8848021
PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1REACTOMER-HSA-8849469
Regulation of TP53 ActivityREACTOMER-HSA-5633007
Regulation of TP53 Expression and DegradationREACTOMER-HSA-6806003
Regulation of TP53 DegradationREACTOMER-HSA-6804757
Regulation of TP53 Activity through Association with Co-factorsREACTOMER-HSA-6804759
Regulation of TP53 Activity through AcetylationREACTOMER-HSA-6804758
EGFR tyrosine kinase inhibitor resistanceKEGGko01521
Platinum drug resistanceKEGGko01524
Endocrine resistanceKEGGko01522
Platinum drug resistanceKEGGhsa01524
EGFR tyrosine kinase inhibitor resistanceKEGGhsa01521
Endocrine resistanceKEGGhsa01522
Breast cancerKEGGko05224
Breast cancerKEGGhsa05224
Downregulation of ERBB2 signalingREACTOMER-HSA-8863795
RAB GEFs exchange GTP for GDP on RABsREACTOMER-HSA-8876198
Interleukin-4 and 13 signalingREACTOMER-HSA-6785807
Fluid shear stress and atherosclerosisKEGGko05418
Fluid shear stress and atherosclerosisKEGGhsa05418
Apelin signaling pathwayKEGGhsa04371

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA134890823PIK3R5GenePathwayassociated
PA134963361MAFAGenePathwayassociated
PA162391083HNF1BGenePathwayassociated
PA162399173PDX1GenePathwayassociated
PA248NFKB1GenePathwayassociated
PA25236BADGenePathwayassociated
PA254NOS3GenePathwayassociated20124951
PA27749ELK1GenePathwayassociated
PA28212FOSGenePathwayassociated
PA29349HNF4AGenePathwayassociated
PA296RELAGenePathwayassociated
PA29932ISL1GenePathwayassociated
PA30006JUNGenePathwayassociated
PA31353MYCGenePathwayassociated
PA31564NEUROD1GenePathwayassociated
PA31600NFKB2GenePathwayassociated
PA33154PDK1GenePathwayassociated22336956
PA33304PIK3C2AGenePathwayassociated20124951, 28362716
PA33305PIK3C2BGenePathwayassociated20124951, 28362716
PA33308PIK3CAGenePathwayassociated28362716
PA33309PIK3CBGenePathwayassociated28362716
PA33310PIK3CDGenePathwayassociated28362716
PA33311PIK3CGGenePathwayassociated28362716
PA33312PIK3R1GenePathwayassociated28362716
PA33313PIK3R2GenePathwayassociated28362716
PA33314PIK3R3GenePathwayassociated28362716
PA337STAT3GenePathwayassociated
PA338STAT5AGenePathwayassociated
PA36042SP1GenePathwayassociated
PA36183STAT1GenePathwayassociated
PA36184STAT2GenePathwayassociated
PA36185STAT4GenePathwayassociated
PA36186STAT5BGenePathwayassociated
PA36380HNF1AGenePathwayassociated
PA443622Carcinoma, Non-Small-Cell LungDiseaseClinicalAnnotationassociatedPD22901187
PA444818Lung NeoplasmsDiseaseClinicalAnnotationassociatedPD
PA447216SchizophreniaDiseaseClinicalAnnotationassociatedPD18855532
PA448803carboplatinChemicalClinicalAnnotationassociatedPD22901187
PA449014cisplatinChemicalClinicalAnnotationassociatedPD22901187
PA451257risperidoneChemicalClinicalAnnotationassociatedPD18855532

References

Pubmed IDYearTitleCitations
371626822024YTHDC2 Retards Cell Proliferation and Triggers Apoptosis in Papillary Thyroid Cancer by Regulating CYLD-Mediated Inactivation of Akt Signaling.2
372775812024Upregulation of SEMP1 Contributes to Improving the Biological Functions of Trophoblast via the PI3K/AKT Pathway in Preeclampsia.0
373395212024HSPA4 regulated glioma progression via activation of AKT signaling pathway.1
374799012024Tumor-suppressive action of miR-30a-5p in lung adenocarcinoma correlates with ABL2 inhibition and PI3K/AKT pathway inactivation.0
375785942024Loss of RACK1 promotes glutamine addiction via activating AKT/mTOR/ASCT2 axis to facilitate tumor growth in gastric cancer.3
376423682024STMN1 promotes cell malignancy and bortezomib resistance of multiple myeloma cell lines via PI3K/AKT signaling.0
377285712024Spinster homolog 2 reduces malignancies of glioblastoma via PTEN/PI3K/AKT pathway.0
379097222024KIRREL promotes the proliferation of gastric cancer cells and angiogenesis through the PI3K/AKT/mTOR pathway.0
379379152024DUSP22 suppresses tumor progression by directly dephosphorylating AKT in non-small cell lung cancer.0
379723892024Extracellular vesicle-encapsulated microRNA-296-3p from cancer-associated fibroblasts promotes ovarian cancer development through regulation of the PTEN/AKT and SOCS6/STAT3 pathways.4
381151792024KLK10 promotes the progression of KRAS mutant colorectal cancer via PAR1-PDK1-AKT signaling pathway.0
381418892024SOD3 regulates FLT1 to affect bone metabolism by promoting osteogenesis and inhibiting adipogenesis through PI3K/AKT and MAPK pathways.0
381720812024IRS1 promotes thyroid cancer metastasis through EMT and PI3K/AKT pathways.0
381723542024FOXM1 transcriptional regulation of RacGAP1 activates the PI3K/AKT signaling pathway to promote the proliferation, migration, and invasion of cervical cancer cells.1
381859042024PAX2 is regulated by estrogen/progesterone through promoter methylation in endometrioid adenocarcinoma and has an important role in carcinogenesis via the AKT/mTOR signaling pathway.0

Citation

Daniela Etro ; Silvia Missiroli ; Francesca Buontempo ; Luca Maria Neri ; Silvano Capitani

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

Atlas Genet Cytogenet Oncol Haematol. 2009-05-01

Online version: http://atlasgeneticsoncology.org/gene/355/css/cancer-prone-explorer/js/lib/bootstrap.min.js