Disease relevance of AKT1

• A survey of 225 human tumors for changes involving AKT1 led to the discovery of a 20-fold amplification of this gene in one of the five gastric adenocarcinomas tested [1].
• Confocal microscopy performed on transfected human breast cancer cells showed that unlike AKT1, AKT2 protein predominantly localized adjacent to the collagen IV matrix during cellular attachment [2].
• Amplification and overexpression of AKT1 was detected in a single case of gliosarcoma [3].
• Lentivirus constructs were used to stably express constitutively active AKT1 or AKT2 in GIST cells to study the role of AKT signaling in metabolism and cell survival [4].
• Because impaired insulin signalling is a major hallmark of Type II (non-insulin-dependent) diabetes mellitus, we considered whether the AKT1 gene could be a candidate gene involved in susceptibility of this condition [5].
• In this review, the role of AKT in thyroid cancer development and progression are discussed with a focus on areas of current debate in the literature [6].
• Our results further showed that AKT1 induced lung cancer cells to become resistant to CDDP through the mammalian target of the rapamycin (mTOR) signaling pathway [7].

Psychiatry related information on AKT1

• CONCLUSIONS: The replication of association of variants in the AKT1 gene in a family sample with similar ethnical background as in the original study adds further evidence for involvement of AKT1 in development of schizophrenic disorders [8].
• Behavioral experiments show that intradermal injection of a PI3K (upstream of PKB/Akt) inhibitor, wortmannin, dose-dependently inhibits the changes in exploratory behavior evoked by capsaicin injection [9].
• In the search for neuroprotective factors in Huntington's disease, we found that insulin growth factor 1 via activation of the serine/threonine kinase Akt/PKB is able to inhibit neuronal death specifically induced by mutant huntingtin containing an expanded polyglutamine stretch [10].
• Because lithium is an effective mood stabilizer for bipolar disorder patients, AKT1 is an interesting candidate for further investigation [11].
• Here, we report selective down regulation of the serine/threonine kinase, Akt/PKB, concurrent with elevated endogenous GSK3beta kinase activity in familial Alzheimer's disease beta-amyloid precursor protein expressing human embryonic kidney (HEK) and familial Alzheimer's disease presenilin lymphoblast cells [12].

High impact information on AKT1

• Recent biochemical studies suggested that TORC2 is the elusive PDK2 for Akt/PKB Ser473 phosphorylation in the hydrophobic motif [13].
• Consistent with this proposal, we also show 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 [14].
• Here, we report that mTOR inhibition induced apoptosis of epithelial cells and the complete reversal of a neoplastic phenotype in the prostate of mice expressing human AKT1 in the ventral prostate [15].
• Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27(Kip1) by PKB/Akt-mediated phosphorylation in breast cancer [16].
• Here we show that activation of protein kinase B (PKB)/Akt, contributes to resistance to antiproliferative signals and breast cancer progression in part by impairing the nuclear import and action of p27 [17].

Chemical compound and disease context of AKT1

• In contrast to breast cancer cells, this increased sensitivity to 17-AAG does not result from cell dependence on AKT1 activity [18].
• Gonadotropin-releasing hormone induces apoptosis of prostate cancer cells: role of c-Jun NH2-terminal kinase, protein kinase B, and extracellular signal-regulated kinase pathways [19].
• Muscarinic receptors mediate phospholipase C-dependent activation of protein kinase B via Ca2+, ErbB3, and phosphoinositide 3-kinase in 1321N1 astrocytoma cells [20].
• Transfection of HeLa cells with a dominant negative mutant of Akt1 or pretreatment of wild-type HeLa cells with the specific PI3K inhibitor LY294002 significantly suppresses viral RNA expression, as reflected in diminished viral capsid protein expression and viral release [21].
• Differential roles of phosphoinositide-dependent protein kinase-1 and akt1 expression and phosphorylation in breast cancer cell resistance to Paclitaxel, Doxorubicin, and gemcitabine [22].

Biological context of AKT1

• The AKT1, AKT2, and AKT3 kinases have emerged as critical mediators of signal transduction pathways downstream of activated tyrosine kinases and phosphatidylinositol 3-kinase [23].
• Two human homologues of the v-akt oncogene, AKT1 and AKT2, were cloned [1].
• Finally, the LCLs in the lowest apoptotic response group have the highest concentration of AKT1 protein and all harbor a haplotype in AKT1 that is present in Caucasians but absent in African Americans [24].
• The assay is capable of detecting significant effects of SNPs in two genes, MDM2 and AKT1, whose products are involved in controlling the p53 pathway and cellular response to DNA damage, suggesting that these data and this assay can be used to identify novel SNPs in other genes whose products impact the cellular response to radiation [24].
• Furthermore, the expression of activated AKT1 inhibits MLK3-mediated cell death in a manner dependent on serine 674 phosphorylation [25].

Anatomical context of AKT1

• AKT1 Provides an Essential Survival Signal Required for Differentiation and Stratification of Primary Human Keratinocytes [26].
• It has been observed that the expression levels of AKT1, AKT2, and AKT3 vary, but the levels of phospho-Ser473 AKT and phospho-Thr308 AKT are quite unique in these cancer cell lines, and that CL-1 cells have the highest basal levels of AKT activation among these cell lines [27].
• The AKT1 gene has been localized to human chromosome 14, band q32, proximal to the heavy-chain immunoglobulin locus (IGHM), by analysis of human-hamster somatic cell hybrids and by in situ hybridization [28].
• As a cellular model system we used Chinese Hamster Ovary (CHO) cells that had been stably transfected with human insulin receptor (hIR) and an AKT1-enhanced green fluorescent protein (EGFP) fusion construct [29].
• METHODS AND RESULTS: To identify the physiological role of the kinase in normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR), we used adenoviral vectors to transfer the human AKT1 gene selectively to the common carotid endothelium [30].

Associations of AKT1 with chemical compounds

• Importantly, expression of constitutively active AKT1 or AKT2 does not rescue cells from the imatinib-mediated apoptosis although glucose uptake was not blocked, suggesting that the potential therapeutic effect of imatinib is independent of AKT activity and glucose deprivation [4].
• AIMS/HYPOTHESIS: AKT1, a serine/threonine protein kinase, is an important downstream target of the insulin-signalling pathway, with both anti-apoptotic and peripheral metabolic effects [5].
• The EGFR kinase inhibitor PD158780 reduced the constitutive phosphorylation of the receptor and Erk but not that of AKT1 [31].
• Our results indicate that the combination of cyclosporin A and Taxol is effective in the reversal of Taxol resistance through the inhibition of PI3 kinase-AKT1 pathway [32].
• In vitro, endothelial vasorelaxations to acetylcholine, isoproterenol, and insulin were blunted in control carotids from SHR compared with WKY rats, and human AKT1 overexpression corrected these responses [30].
• The association of AR with Akt1 was inhibited by the anti-androgen, bicalutamide, but was not affected by inhibition of phosphoinositide 3-kinase (PI3K) [33].
• Ca(2+).CaM competes with phosphatidylinositol 3,4,5-trisphophate for interaction with the PH domain of human AKT1 [34].

Physical interactions of AKT1

• Altogether, our data demonstrate that Akt1 participates in a negative regulatory feedback loop by interacting with the JIP1 scaffold protein [35].
• Here we provide evidence that PKC theta is physically and functionally coupled to Akt1 in this signaling pathway [36].
• In this manner, RAC is closely juxtaposed to the cell membrane of the target cell and is anchored in this position via binding of the remaining antigen-combining site to p40 prostate restricted antigen [37].
• PKB/Akt interacts with inosine-5' monophosphate dehydrogenase through its pleckstrin homology domain [38].
• A yeast-based two-hybrid system was employed which identified inosine-5' monophosphate dehydrogenase (IMPDH) type II as specifically interacting with PKB/Akts PH domain [38].

Enzymatic interactions of AKT1

• METHODS: Expression of EGFR and ligand-independent EGFRvIII mutant proteins and of phosphorylated protein kinase B (PKB)/Akt in specimens from glioma patients were assessed by immunohistochemistry [39].
• Similarly, activation of the AR by phosphorylated protein kinase B, Akt, has also been reported in prostate cancer [40].
• FKHR is phosphorylated by protein kinase B (PKB) at Thr24, Ser256 and Ser319 in response to growth factors, stimulating the nuclear exit and inactivation of this transcription factor [41].
• We have shown recently that DNA damage effector kinase Chk1 is phosphorylated in vitro by protein kinase B/Akt (PKB/Akt) on serine 280 [42].
• We also showed that DAP3 is phosphorylated by kinase Akt (PKB), and active Akt can nullify apoptosis induction by DAP3 [43].

Regulatory relationships of AKT1

• The tumor suppressor PTEN positively regulates macroautophagy by inhibiting the phosphatidylinositol 3-kinase/protein kinase B pathway [44].
• Likewise, radiation-induced autophosphorylation of DNA-PKcs at Thr2609 was only blocked in A549 cells by these two inhibitors and AKT1 small interfering RNA transfection [45].
• These results indicate that human Akt3 is regulated similarly to Akt1 and Akt2 [46].
• Protein kinase B-alpha inhibits human pyruvate dehydrogenase kinase-4 gene induction by dexamethasone through inactivation of FOXO transcription factors [47].
• There is growing evidence that epidermal growth factor (EGF) activates Akt/protein kinase B (PKB) in a phosphoinositide 3-OH kinase (PI3K)-dependent manner, but it is not yet clear which Akt isoforms are involved in this signal transduction pathway [48].
• We find that, in viral warts (papillomas) and HPV gene-induced epidermal tumors, AKT activity can be activated focally by up-regulation and phosphorylation of the AKT2 isoform [49].
• Inhibition of ERK or AKT diminished CG-induced MMP-2 expression [50].

Other interactions of AKT1

• This indicates that the major function of C. elegans PDK1 is to transduce signals from AGE-1 to AKT-1 and AKT-2 [51].
• Somatic mutations of PTEN are found in a number of human malignancies, and loss of expression, or mutational inactivation of PTEN, leads to the constitutive activation of protein kinase B (PKB)/Akt via enhanced phosphorylation of Thr-308 and Ser-473 [52].
• Decreased phosphorylation of protein kinase B and extracellular signal-regulated kinase in neutrophils from patients with myelodysplasia [53].
• Western blots revealed that p53 was stabilized in HCT116 PTEN(-/-) cells via an Akt1-dependent and p14(ARF)-independent mechanism [54].
• During insulin stimulation, IRS-1 and IRS-2 strongly bound p85alpha/beta, which activated phosphatidylinositol (PI) 3-kinase, protein kinase B (PKB)/Akt, and p70(s6k), and promoted the phosphorylation of BAD [55].

Analytical, diagnostic and therapeutic context of AKT1

• Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: amplification of AKT1 in a primary human gastric adenocarcinoma [1].
• To assess directly the impact of increased AKT activity on prostate cancer progression, an activated hAKT1 mutant was overexpressed in LNCaP cells, resulting in a 6-fold increase in xenograft tumor growth [56].
• Increased phosphorylation of PKB and PKB substrates was identified in neurons and other cell types by immunohistochemistry in both humans and rats [57].
• Signal transducers and activators of transcription 3 (STAT3), Protein Kinase B/AKT and Map Kinases (MAPKs), which are activated by a variety of factors, modulate cell proliferation, apoptosis and other biological activities [58].
• As a target for drug discovery, we have expressed and purified an active Akt1 enzyme from a recombinant baculovirus-infected Sf9 cell culture [59].

References