Disease relevance of Akt1

• Akt1 regulates pathological angiogenesis, vascular maturation and permeability in vivo [1].
• Even haplodeficiency of Akt1 was sufficient to markedly attenuate the development of high-grade prostate intraepithelial neoplasia (PIN) and endometrial carcinoma [2].
• Dwarfism, impaired skin development, skeletal muscle atrophy, delayed bone development, and impeded adipogenesis in mice lacking Akt1 and Akt2 [3].
• Akt1 deficiency had a profound effect on endometrium and prostate neoplasia, two types of human cancer, in which PTEN is frequently mutated, and also affected thyroid and adrenal medulla tumors and intestinal polyps [2].
• Akt1 knockout (Akt1-/-) mice also have reduced endothelial progenitor cell (EPC) mobilization in response to ischemia, and reintroduction of WT EPCs, but not EPCs isolated from Akt1-/- mice, into WT mice improves limb blood flow after ischemia [4].
• In the vessel wall, the loss of Akt1 increases inflammatory mediators and reduces eNOS phosphorylation, suggesting that Akt1 exerts vascular protection against atherogenesis [5].
• Akt1 governs MEC polarity, migratory directionality and breast cancer onset induced by ErbB2 in vivo [6].

Psychiatry related information on Akt1

• These data support the involvement of GSK-3 as an important mediator of DA and lithium action in vivo and suggest that modulation of the Akt/GSK-3 pathway might be relevant to DA-related disorders, such as attention deficit hyperactivity disorder and schizophrenia [7].
• Here we show that PS1, a protein involved in familial Alzheimer's disease (FAD), promotes cell survival by activating the PI3K/Akt cell survival signaling [8].
• Recent investigations have shown that three major striatal-signaling pathways (protein kinase A/DARPP-32, Akt/glycogen synthase kinase 3, and ERK) are involved in the regulation of locomotor activity by the monoaminergic neurotransmitter dopamine [9].
• Here we demonstrate in precise genetic Huntington's disease mouse and striatal cell models that these early phenotypes are associated with activation of the Akt pro-survival signaling pathway [10].
• This study tested if sodium valproate or lithium, two agents used to treat bipolar mood disorder, altered the regulatory phosphorylations of Akt or glycogen synthase kinase-3beta (GSK3beta) in human neuroblastoma SH-SY5Y cells [11].

High impact information on Akt1

• Our observations show that intestinal polyposis is initiated by PTEN-deficient ISCs that undergo excessive proliferation driven by Akt activation and nuclear localization of beta-catenin [12].
• Snails, Swiss, and serum: the solution for Rac 'n' Rho [13].
• Nuclear exclusion of the forkhead transcription factor FOXO3a by protein kinase Akt contributes to cell survival [14].
• Forced activation of mTOR through upstream regulator Akt also increased ABI in colon cancer cells [15].
• Loner and ARF6, which also control the proper membrane localization of another small GTPase, Rac, are key components of a cellular apparatus required for myoblast fusion and muscle development [16].

Chemical compound and disease context of Akt1

• Our findings show that PDK1 may be a superior alternative to Akt1 as a target for sensitizing breast cancer cells to chemotherapeutic agents, particularly gemcitabine [17].
• Combinatorial activities of Akt and B-Raf/Erk signaling in a mouse model of androgen-independent prostate cancer [18].
• PTEN/Akt signaling through epidermal growth factor receptor is prerequisite for angiogenesis by hepatocellular carcinoma cells that is susceptible to inhibition by gefitinib [19].
• Previously, we showed that the green tea polyphenol epigallocatechin 3-gallate (EGCG) inhibits growth of NF639 Her-2/neu-driven breast cancer cells via reducing receptor autophosphorylation and downstream Akt and NF-kappaB activities [20].
• RESULTS: LY294002 demonstrated a remarkable growth-inhibitory and apoptosis-inducing effect in these colon cancer cell lines, with decreased expression of phosphorylated Akt (Ser(473)) [21].

Biological context of Akt1

• Angiogenic responses in three distinct in vivo models were enhanced in Akt1(-/-) mice; these enhanced responses were associated with impairment of blood vessel maturation and increased vascular permeability [1].
• Growth retardation and increased apoptosis in mice with homozygous disruption of the Akt1 gene [22].
• Overall, the combined deletion of Akt1 and Akt2 establishes in vivo roles for Akt in cell proliferation, growth, and differentiation [3].
• However, Akt1(-/-) mice do not display a diabetic phenotype [22].
• In addition, the life span of Akt1(-/-) mice, upon exposure to genotoxic stress, is shorter [22].

Anatomical context of Akt1

• Re-expression of TSP-1 and TSP-2 in mice transplanted with wild-type bone marrow corrected the angiogenic abnormalities in Akt1(-/-) mice [1].
• Regulation of pancreatic beta-cell growth and survival by the serine/threonine protein kinase Akt1/PKBalpha [23].
• Finally, Akt1(-/-) mouse embryo fibroblasts (MEFs) are more susceptible to apoptosis induced by TNF, anti-Fas, UV irradiation, and serum withdrawal [22].
• Increased spontaneous apoptosis in testes, and attenuation of spermatogenesis is observed in Akt1(-/-) male mice [22].
• The resulting higher Akt1 activity leads to increased keratinocyte survival following growth factor deprivation or anoikis [24].

Associations of Akt1 with chemical compounds

• Increased spontaneous apoptosis is also observed in the thymi of Akt1(-/-) mice, and Akt1(-/-) thymocytes are more sensitive to apoptosis induced by gamma-irradiation and dexamethasone [22].
• Loss of Akt1 alone slightly impaired insulin-mediated hexose transport activity but had no detectable effect on glycogen synthase kinase (GSK)-3 phosphorylation [25].
• Importantly, UV-induced increases in p70(S6k) phosphorylation at Thr(389) and Thr(421)/Ser(424) were dramatically inhibited by pretreatment of cells with rapamycin, LY294002, or PD98059, whereas overexpression of dominant-negative mutants of PKClambda/iota and Akt1 did not inhibit p70(S6k) phosphorylation at Thr(389) and Thr(421)/Ser(424) [26].
• Akt isoforms 1-3 and a kinase-dead Akt1 (K179A) mutant were phosphorylated in a phosphatidylinositol 3,4,5-trisphosphate-dependent manner at Ser-473 in an in vitro reaction containing this novel adipocyte subcellular fraction [27].
• SH2-containing inositol phosphatase 2 predominantly regulates Akt2, and not Akt1, phosphorylation at the plasma membrane in response to insulin in 3T3-L1 adipocytes [28].
• These findings demonstrate that Akt1 is required in an isoform-specific manner for orchestrating many of the developmental changes in cellular metabolism that occur at the onset of lactation and establish a role for Akt1 in glucose metabolism [29].
• Expression of myrAkt1 corrected the phenotype of Akt1(-/-) fibroblasts thus showing that Akt1 regulates fibronectin assembly through activation of integrin alpha(5)beta(1) [30].
• THP-1 cells adaptively adjusted to LeTx and overrode cell cycle arrest by activating the phosphatidylinositol 3-kinase/Akt signaling pathway [31].
• Knockdown of hnRNP A1 also renders quiescent Akt-containing cells sensitive to rapamycin-induced G(1) arrest [32].
• We also show that the Akt/CDK2 pathway is constitutively activated by some anticancer drugs, such as methotrexate and docetaxel, and under these conditions it promotes, rather than represses, cell death [33].
• Our findings support a critical role for PKB in the hormonal regulation of glucose and system A amino acid uptake and indicate that use of Akti and expression of the drug-resistant kinase will be valuable tools in delineating cellular PKB functions [34].

Physical interactions of Akt1

• We have used a combination of 14-3-3 binding and recognition by an antibody to the phosphorylation consensus of the enzyme to identify and isolate one of the major substrates of Akt, which is also a 14-3-3 binding protein [35].
• Treatment with LY294002 or introduction of dn-Akt severely diminished DNA binding of Runx2 and Runx2-dependent transcription, whereas forced expression of myrAkt enhanced them [36].
• Tcl1 interacts physically with Akt, increases its kinase activity and facilitates its transport to the nucleus [37].
• Mas oncogene signaling and transformation require the small GTP-binding protein Rac [38].
• Interestingly, FKHRL1 co-immunoprecipitated with Akt in PC12 cells, indicating that these two proteins can associate in these cells [39].

Enzymatic interactions of Akt1

• Constitutive activation of Akt phosphorylated and inhibited the transcription factor Foxo3a [40].
• We show here that withdrawal of all survival factors from MK-PT cells is associated with a progressive increase in the activity of extracellular signal-regulated kinase-1 and -2 (ERK1/2) and a progressive decrease in phosphorylated Akt, a kinase critical to cell survival [41].
• The serine/threonine protein kinase Akt (protein kinase B) phosphorylates endothelial cell nitric oxide synthase (eNOS) and enhances its ability to generate nitric oxide (NO) [42].
• Although purified DNA-PK could phosphorylate a peptide derived from Akt that contains amino acid Ser-473, it could not phosphorylate full-length Akt2 [43].
• However, GSK-3 is also inhibited when it is phosphorylated by Akt, a downstream target of phosphatidylinositol 3-kinase (PI3K) [44].

Regulatory relationships of Akt1

• CD28-dependent activation of protein kinase B/Akt blocks Fas-mediated apoptosis by preventing death-inducing signaling complex assembly [45].
• Overexpression of either p55alpha or p50alpha reduces levels of activated Akt [46].
• We propose a novel mechanism in which Stat3 regulates apoptosis by inducing expression of distinct PI(3)K regulatory subunits to downregulate PI(3)K-Akt-mediated survival signalling [46].
• Overexpression of Gab2 enhanced the phosphorylation state of Akt, but not of ERK [47].
• In fact, Akt was constitutively activated in the absence of EGF in AD3 cells [19].

Other interactions of Akt1

• These findings establish a crucial role of an Akt-thrombospondin axis in angiogenesis [1].
• Rho, Rac, and Cdc42 control signal transduction pathways that are essential for cell growth [48].
• These early events lead to activation of the serine-threonine protein kinase Akt, also known as protein kinase B. We show that mice deficient in Akt2 are impaired in the ability of insulin to lower blood glucose because of defects in the action of the hormone on liver and skeletal muscle [49].
• Accordingly, the signaling pathway involving IkappaB-alpha, a cytoplasmic protein that binds NF-kappaB and inhibits its nuclear translocation, appears to be regulated by Akt in mast cells [50].
• Importantly, Akt regulates the production and secretion of IL-2 and TNF-alpha in FcepsilonRI-stimulated mast cells [50].

Analytical, diagnostic and therapeutic context of Akt1

• The intracellular localization of Tcl1 and Akt1 in mouse fibroblasts was investigated by immunofluorescence [51].
• In a rabbit hind limb model of vascular insufficiency, intramuscular activation of Akt1 signaling promoted collateral and capillary vessel formation and an accompanying increase in limb perfusion [52].
• Like Akt1, Akt3 is not required for the maintenance of normal carbohydrate metabolism but is essential for the attainment of normal organ size [53].
• Isografts of either PDK1- or PKCalpha-expressing cells but not Akt1-expressing cells in syngeneic mice led to formation of poorly differentiated mammary carcinomas [54].
• Western blot demonstrated increased expression of Akt1 (by fivefold, p<0.01) and p44 MAP kinase (by sixfold, p<0.01), and decreased activation of caspase-3 (by 30%, p<0.05) [55].

References