*164730	Links
V-AKT MURINE THYMOMA VIRAL ONCOGENE HOMOLOG 1; AKT1

Alternative titles; symbols

ONCOGENE AKT1
PROTEIN KINASE B-ALPHA
PKB-ALPHA
RAC SERINE/THREONINE PROTEIN KINASE

Gene map locus 14q32.3

TEXT

DESCRIPTION

Phosphoinositide 3-kinases, or PI3Ks (see PIK3CA; 171834), generate specific inositol lipids implicated in the regulation of cell growth, proliferation, survival, differentiation, and cytoskeletal changes. One of the best characterized targets of PI3K lipid products is the protein kinase AKT, or protein kinase B (PKB). In quiescent cells, PKB resides in the cytosol in a low-activity conformation. Upon cellular stimulation, PKB is activated through recruitment to cellular membranes by PI3K lipid products and by phosphorylation by 3-prime phosphoinositide-dependent kinase-1 (PDPK1; 605213). For a review of the mechanism that activates PKB and the downstream actions of this multifunctional kinase, see Vanhaesebroeck and Alessi (2000). For a review of the possible role of PKB in glucose transport, see Hajduch et al. (2001).

CLONING

The AKT oncogene was isolated from the directly transforming murine retrovirus AKT8, which was isolated from an AKR mouse thymoma cell line. Staal (1987) cloned the human cellular homolog, AKT1. They found a 20-fold amplification of the AKT1 gene in 1 of 5 gastric adenocarcinomas tested.

Protein phosphorylation is a fundamental process for the regulation of cellular functions. The coordinated action of both protein kinases and phosphatases controls the levels of phosphorylation and, hence, the activity of specific target proteins. One of the predominant roles of protein phosphorylation is in signal transduction, where extracellular signals are amplified and propagated by a cascade of protein phosphorylation and dephosphorylation events. Two of the best characterized signal transduction pathways involve the cAMP-dependent protein kinase (188830) and protein kinase C (PKC; 176960). Each pathway uses a different second-messenger molecule to activate the protein kinase, which, in turn, phosphorylates specific target molecules. Extensive comparisons of kinase sequences defined a common catalytic domain, ranging from 250 to 300 amino acids. This domain contains key amino acids conserved between kinases and are thought to play an essential role in catalysis. Jones et al. (1991) isolated a partial cDNA that encodes a protein kinase they termed rac (related to the A and C kinases). DNA sequencing identified an open reading frame of 1,440 bp encoding a protein of 480 amino acids. In an in vitro translation system that used RNA transcribed from cloned cDNAs, they demonstrated the synthesis of a protein of corresponding size. The predicted protein contains consensus sequences characteristic of a protein kinase catalytic domain and shows 73 and 68% similarity to protein kinase C and cAMP-dependent protein kinase, respectively.

GENE FUNCTION

The serine-threonine protein kinase encoded by the AKT1 gene is catalytically inactive in serum-starved primary and immortalized fibroblasts. Franke et al. (1995) showed that AKT1 and the related AKT2 (164731) are activated by platelet-derived growth factor (PDGF; 190040). The activation is rapid and specific, and is abrogated by mutations in the pleckstrin homology domain of AKT1. Other experiments showed that the activation also depends on PDGFRB (173410) tyrosines 740 and 751, which bind PIK3 upon phosphorylation.

Dudek et al. (1997) demonstrated that AKT is important for the survival of cerebellar neurons. Thus, the 'orphan' kinase moved center stage as a crucial regulator of life and death decisions emanating from the cell membrane (Hemmings, 1997). The work of Dudek et al. (1997) delineated a signaling pathway by which insulin-like growth factor-1 (IGF1; 147440) promotes the survival of cerebellar neurons. IGF1 activation of PIK3 triggered the activation of 2 protein kinases, AKT and the p70 ribosomal protein S6 kinase (p70-RPS6K). Experiments with pharmacologic inhibitors, as well as expression of wildtype and dominant-inhibitory forms of AKT, demonstrated that AKT but not p70-RPS6K mediates PIK3-dependent survival. The findings suggested that in the developing nervous system AKT is a critical mediator of growth factor-induced neuronal survival. Franke et al. (1997) defined the specific mechanisms by which lipid products of PIK3 regulate AKT.

Ozes et al. (1999) showed that AKT1 is involved in the activation of NFKB1 (164011) by TNF (191160), following the activation of PIK3. Constitutively active AKT1 induces NFKB1 activity, mediated by phosphorylation of IKBKA (600664) at threonine 23, which can be blocked by activated NIK (604655). Conversely, NIK activation of NFKB, mediated by phosphorylation of IKBKA at serine 176, is blocked by an AKT1 mutant lacking kinase activity (i.e., kinase dead AKT), indicating that both AKT1 and NIK are necessary for TNF activation of NFKB1 through the phosphorylation of IKBKA. IKBKB (IKKB; 603258) is not phosphorylated by either NIK or AKT1 and is apparently differentially regulated.

Most proliferating cells are programmed to undergo apoptosis unless specific survival signals are provided. PDGF promotes cellular proliferation and inhibits apoptosis. Romashkova and Makarov (1999) showed that PDGF activates the RAS/PIK3/AKT1/IKBKA/NFKB1 pathway. In this pathway, NFKB1 does not induce c-myc and apoptosis, but instead induces putative antiapoptotic genes. In response to PDGF, AKT1 transiently associates with IKBK and induces IKBK activation. The authors suggested that under certain conditions PIK3 may activate NFKB1 without the involvement of IKBA (164008) or IKBB (604495) degradation.

Survival factors can suppress apoptosis in a transcription-independent manner by activating the serine/threonine kinase AKT1, which then phosphorylates and inactivates components of the apoptotic machinery, including BAD (603167) and caspase-9 (602234). Brunet et al. (1999) demonstrated that AKT1 also regulates the activity of FKHRL1 (FOXO3A; 602681), a member of the forkhead family of transcription factors. In the presence of survival factors, AKT1 phosphorylates FKHRL1, leading to the association of FKHRL1 with 14-3-3 proteins and its retention in the cytoplasm. Survival factor withdrawal leads to FKHRL1 dephosphorylation, nuclear translocation, and target gene activation. Within the nucleus, FKHRL1 most likely triggers apoptosis by inducing the expression of genes that are critical for cell death, such as the TNFSF6 gene (134638).

Using in vitro pull-down assays, Powell et al. (2002) showed that recombinant 14-3-3-zeta (601288) interacted directly with both recombinant and endogenous PKB within embryonic kidney cell lysates. They found that recombinant PKB phosphorylated 14-3-3-zeta in an in vitro kinase assay, and transfection of active PKB into embryonic kidney cells resulted in phosphorylation of 14-3-3-zeta. By mutation analysis, Powell et al. (2002) determined that the phosphate acceptor was serine-58. They also showed that phosphorylation did not result in 14-3-3-zeta dimerization.

Fulton et al. (1999) demonstrated that AKT directly phosphorylated eNOS (NOS3; 163729) and activated the enzyme leading to nitric oxide (NO) production, whereas eNOS mutated at a putative AKT phosphorylation site was resistant to phosphorylation and activation by AKT. Activated AKT increased basal nitric oxide release from endothelial cells, and activation-deficient AKT attenuated NO production stimulated by VEGF (192240). Thus, Fulton et al. (1999) concluded the eNOS is an AKT substrate linking signal transduction by AKT to the release of the gaseous second messenger nitric oxide. Dimmeler et al. (1999) demonstrated that AKT mediates the activation of eNOS, leading to increased nitric oxide production. Inhibition of the PIK3 AKT pathway or mutation of the AKT site on eNOS protein at serine-1177 attenuated the serine phosphorylation and prevented the activation of eNOS. Mimicking the phosphorylation of ser1177 directly enhanced enzyme activity and altered the sensitivity of the enzyme to calcium, rendering its activity maximal at subphysiologic concentrations of calcium. Thus, phosphorylation of eNOS by AKT represented a novel calcium-independent regulatory mechanism for activation of eNOS.

Lee et al. (2001) showed that sphingosine 1-phosphate (S1P)-induced endothelial cell migration requires the AKT-mediated phosphorylation of the G protein-coupled receptor (GPCR) EDG1 (601974). Activated AKT binds to EDG1 and phosphorylates the third intracellular loop at the thr236 residue. Transactivation of EDG1 by AKT is not required for Gi-dependent signaling but is indispensable for RAC activation, cortical actin assembly, and chemotaxis. Indeed, a thr236-to-ala EDG1 mutant sequestered AKT and acted as a dominant-negative GPCR to inhibit S1P-induced RAC activation, chemotaxis, and angiogenesis. Transactivation of GPCRs by AKT may constitute a specificity switch to integrate rapid G protein-dependent signals into long-term cellular phenomena such as cell migration.

Furnari et al. (1998) demonstrated that PTEN (601728) can dephosphorylate PIP3, the major product of PIK3. PIP3, in turn, is required for translocation of AKT to the cell membrane, where it is phosphorylated and activated by upstream kinases.

Dahia et al. (1999) found that PTEN and phosphorylated AKT levels were inversely correlated in a large majority of samples with primary acute leukemias and non-Hodgkin lymphomas as well as in cell lines from these malignancies.

Weng et al. (2001) demonstrated increased PTEN-mediated cell death of MCF-7 breast cancer cells cultured in low levels of growth factors. The caspase 9-specific inhibitor ZVAD blocked PTEN-induced cell death without altering the effect of PTEN on cell cycle distribution. Overexpression of AKT that contained a dominant-negative acting lys179-to-met mutation induced more cell death but had less effect on the cell cycle than overexpression of PTEN. The authors suggested that the apoptotic MCF-7 cells induced by the overexpression of PTEN were not derived from G1-arrested cells. They further hypothesized that the effect of PTEN on cell death is mediated through the PIK3/AKT pathway, whereas PTEN-mediated cell cycle arrests depend on both PIK3/AKT-dependent and -independent pathways.

By mutation and immunoprecipitation analyses, Maira et al. (2001) established that CTMP (606388) forms a complex with the C-terminal regulatory domain of PKB, but not with full-length PKB. Functional and Western blot analyses showed that CTMP inhibits the phosphorylation of PKB and in turn inhibits the phosphorylation of glycogen synthase kinase-3-beta (GSK3B; 605004), a PKB-mediated phosphorylation event. Antisense inhibition of CTMP increased the ability of PKB to activate its downstream effectors. Maira et al. (2001) proposed that CTMP negatively regulates PKB by directly binding to it and preventing its phosphorylation, whereas PTEN (601728) inhibits PKB indirectly by reducing the amounts of phosphatidylinositol trisphosphate at the cell membrane.

Inoki et al. (2002) demonstrated that Akt1 phosphorylates Tsc2 (191092), thereby disrupting interaction between Tsc2 and Tsc1 (605284). Potter et al. (2002) described a similar relationship between Akt and Tsc2 in Drosophila. Inoki et al. (2002) showed that the Tsc1-Tsc2 complex inhibits the mammalian target of rapamycin (MTOR; 601231), leading to inhibition of p70 ribosomal S6 kinase-1 (608938) and activation of eukaryotic translation initiation factor 4E-binding protein-1 (EIF4EBP1; 602223).

Shin et al. (2002) demonstrated a novel mechanism of AKT-mediated regulation of the CDK inhibitor p27(KIP1) (600778). Blockade of HER2/NEU (164870) in tumor cells inhibited AKT kinase activity and upregulated nuclear levels of p27(KIP1). Recombinant AKT and AKT precipitated from tumor cells phosphorylated wildtype p27 in vitro. P27 contains an AKT consensus RXRXXT(157)D within its nuclear localization motif. Active (myristoylated) AKT phosphorylated wildtype p27 in vivo but was unable to phosphorylate a T157A-p27 mutant. Wildtype p27 localized in the cytosol and nucleus, whereas the mutant p27 localized exclusively in the nucleus and was resistant to nuclear exclusion by AKT. Expression of phosphorylated AKT in primary human breast cancers statistically correlated with the expression of p27 in tumor cytosol. Shin et al. (2002) concluded that AKT may contribute to tumor cell proliferation by phosphorylation and cytosolic retention of p27, thus relieving CDK2 (116953) from p27-induced inhibition.

Liang et al. (2002) demonstrated that AKT1 phosphorylates p27, impairs the nuclear import of p27, and opposes cytokine-mediated G1 arrest. In cells transfected with constitutively active AKT, wildtype p27 mislocalized to the cytoplasm, but mutant p27 was nuclear. In cells with activated AKT, wildtype p27 failed to cause G1 arrest, while the antiproliferative effect of mutant p27 was not impaired. Cytoplasm p27 was seen in 41% (52 of 128) primary human breast cancers in conjunction with AKT activation and was correlated with a poor patient prognosis. Liang et al. (2002) concluded that their data showed a novel mechanism whereby AKT impairs p27 function that is associated with an aggressive phenotype in human breast cancer.

Viglietto et al. (2002) independently demonstrated that AKT regulates cell proliferation in breast cancer cells by preventing p27(KIP1)-mediated growth arrest. They also showed that threonine at position 157 is an AKT phosphorylation site and causes retention of p27(KIP1) in the cytoplasm, precluding p27(KIP1)-induced G1 arrest.

Humbert et al. (2002) found that IGF1 and AKT inhibited mutant huntingtin (143100)-induced cell death and formation of intranuclear inclusions of polyQ huntingtin. AKT phosphorylated ser421 of huntingtin with 23 glutamines, and this phosphorylation reduced mutant huntingtin-induced toxicity in primary cultures of rat striatal neurons. Western blot analysis of cerebellum, cortex, and striatum from Huntington disease patients detected the 60-kD full-length AKT protein and a caspase-3 (CASP3; 600636)-generated 49-kD AKT product. In contrast, normal control brain areas expressed little to no 49-kD AKT. Humbert et al. (2002) concluded that phosphorylation of huntingtin through the IGF1/AKT pathway is neuroprotective, and they hypothesized that the IGF1/AKT pathway may have a role in Huntington disease.

Vasko et al. (2004) demonstrated Akt involvement in thyroid cancer progression by investigating 46 cancers, 20 follicular adenomas, and adjacent normal tissue by immunohistochemistry for activated Akt (pAkt), Akt1, -2, and -3, and p27 expression. Akt activation was found in 38 cancers (10 of 10 follicular cancers, 26 of 26 papillary cancers, and 2 of 10 follicular variants of papillary cancer) and in only 4 of 66 normal tissue sections and 2 of 10 benign follicular adenomas. Immunoactive pAkt, correlating with Akt1, was expressed most often in areas of capsular invasion and localized to the cytoplasm in papillary cancers, to the nucleus in follicular cancers, and to both compartments in invasive papillary cancers. Nuclear pAkt and Akt1 were associated with cytoplasmic expression of p27, cell invasion, and migration.

Mangi et al. (2003) genetically engineered rat mesenchymal stem cells using ex vivo retroviral transduction to overexpress Akt1. Transplantation of 5 x 10(6) cells overexpressing Akt into the ischemic rat myocardium inhibited the process of cardiac remodeling by reducing intramyocardial inflammation, collagen deposition, and cardiac myocyte hypertrophy, regenerated 80 to 90% of lost myocardial volume, and completely normalized systolic and diastolic cardiac function. These observed effects were dose (cell number)-dependent. Mesenchymal stem cells transduced with Akt1 restored 4-fold greater myocardial volume than equal numbers of cells transduced with the reporter gene lacZ. Mangi et al. (2003) concluded that mesenchymal stem cells genetically enhanced with Akt1 can repair infarcted myocardium, prevent remodeling, and nearly normalize cardiac performance.

Using a murine lymphoma model, Wendel et al. (2004) demonstrated that Akt promotes tumorigenesis and drug resistance by disrupting apoptosis, and that disruption of Akt signaling using the mTOR inhibitor rapamycin reverses chemoresistance in lymphomas expressing Akt, but not in those with other apoptotic defects. eIF4E (133440), a translational regulator that acts downstream of Akt and mTOR, recapitulated Akt's action in tumorigenesis and drug resistance but was unable to confer sensitivity to rapamycin and chemotherapy. Wendel et al. (2004) concluded that their results established Akt signaling through mTOR and eIF4E as an important mechanism of oncogenesis and drug resistance in vivo and revealed how targeting apoptotic programs can restore drug sensitivity in a genotype-dependent manner.

Hu et al. (2004) investigated the pathologic relationship between phosphorylated AKT, or AKT-p, and FOXO3A (602681) in primary tumors. FOXO3A was excluded from the nuclei of some tumors lacking AKT-p, suggesting an AKT-independent mechanism of regulating FOXO3A localization. Hu et al. (2004) provided evidence for such a mechanism by showing that IKK physically interacted with, phosphorylated, and inhibited FOXO3A independent of AKT and caused proteolysis of FOXO3A via the ubiquitin (see 191339)-dependent proteasome pathway. Cytoplasmic FOXO3A correlated with expression of IKKB or AKT-p in many tumors and was associated with poor survival in breast cancer. Constitutive expression of IKKB promoted cell proliferation and tumorigenesis that could be overridden by FOXO3A. These results suggested that the negative regulation of FOXO factors by IKK is a key mechanism for promoting cell growth and tumorigenesis.

Song et al. (2004) showed that OX40 (600315) engagement sustains activation of PKB and intermediates of PKB signaling pathways, including PI3K, GSK3, and FKHR (FOXO1A; 136533). T cells from mice lacking Ox40 were unable to maintain PKB activity over time, and this loss of activity coincided with cell death. Expression of active PKB in responding Ox40 -/- cells reversed the survival defect. Song et al. (2004) concluded that the duration of signaling needed for long-term survival is much longer than that needed for proliferation.

Cha et al. (2005) showed that AKT phosphorylates EZH2 (601573) at serine-21 and suppresses its methyltransferase activity by impeding EZH2 binding to histone H3 (see 601128), which results in a decrease of lysine-27 trimethylation and derepression of silenced genes. Cha et al. (2005) concluded that their results imply that AKT regulates the methylation activity, through phosphorylation of EZH2, which may contribute to oncogenesis.

Akt/PKB activation requires the phosphorylation of serine-473. Sarbassov et al. (2005) showed that in Drosophila and in human cells TOR and its associated protein rictor (609022) are necessary for serine-473 phosphorylation, and that a reduction in rictor or mTOR expression inhibited an AKT/PKB effector. The rictor-mTOR complex directly phosphorylated Akt/PKB on serine-473 in vitro and facilitated threonine-308 phosphorylation by PDK1.

Trotman et al. (2006) demonstrated that the PML (102578) tumor suppressor prevents cancer by inactivating phosphorylated AKT inside the nucleus. They found in a mouse model that Pml loss markedly accelerated tumor onset, incidence, and progression in Pten (601728) heterozygous mutants, and led to female sterility with features that recapitulate the phenotype of Foxo3a knockout mice. Trotman et al. (2006) showed that PML deficiency on its own leads to tumorigenesis in the prostate, a tissue that is exquisitely sensitive to phosphorylated AKT levels, and demonstrated that PML specifically recruits the AKT phosphatase PP2a (see 603113) as well phosphorylated AKT into PML nuclear bodies. Notably, Trotman et al. (2006) found that PML-null cells are impaired in PP2a phosphatase activity towards AKT, and thus accumulate nuclear phosphorylated AKT. As a consequence, the progressive reduction in PML dose leads to inactivation of FOXO3A-mediated transcription of proapoptotic BIM (603827) and the cell cycle inhibitor p27(KIP1) (600778). Trotman et al. (2006) concluded that their results demonstrate that PML orchestrates a nuclear tumor suppressor network for inactivation of nuclear phosphorylated AKT, and thus highlight the importance of AKT compartmentalization in human cancer pathogenesis and treatment.

BIOCHEMICAL FEATURES

The protein activity of PKB is stimulated by phosphorylation at 2 regulatory sites, thr309 of the activation segment and ser474 of the hydrophobic motif, a conserved feature of many AGC kinases. Yang et al. (2002) provided a molecular explanation for regulation by ser474 phosphorylation by analyzing the crystal structures of the unphosphorylated and thr309-phosphorylated states of the PKB kinase domain. Activation by ser474 phosphorylation occurs via a disorder-to-order transition of the alpha-C helix with concomitant restructuring of the activation segment and reconfiguration of the kinase bilobal structure. These conformational changes are mediated by a phosphorylation-promoted interaction of the hydrophobic motif with a channel on the N-terminal lobe induced by the ordered alpha-C helix and are mimicked by peptides corresponding to the hydrophobic motif of PKB and potently by the hydrophobic motif of PRK2 (602549).

AKT-GSK3B signaling is a target of lithium and as such has been implicated in the pathogenesis of mood disorders. Emamian et al. (2004) provided evidence that this signaling pathway also has a role in schizophrenia (SCZD; 181500). Specifically, they presented convergent evidence for a decrease in ATK1 protein levels and levels of phosphorylation of GSK3B at serine-9 in the peripheral lymphocytes and brains of individuals with schizophrenia; a significant association between schizophrenia and an AKT1 haplotype associated with lower AKT1 protein levels; and a greater sensitivity to the sensorimotor gating-disruptive effect of amphetamine, conferred by AKT1 deficiency. The findings supported the proposal that alterations in AKT1-GSK3B signaling contribute to schizophrenia pathogenesis and identified AKT1 as a potential schizophrenia susceptibility gene. Consistent with this proposal, Emamian et al. (2004) also showed 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.

MAPPING

Staal et al. (1988) mapped the AKT1 gene to chromosome 14q32.3 by analysis of human-hamster somatic cell hybrids and by in situ hybridization of normal human metaphase chromosome spreads with a radioactive AKT1 probe. The AKT1 gene is proximal to the immunoglobulin heavy chain loci. By fluorescence in situ hybridization, Bellacosa et al. (1993) mapped akt to mouse chromosome 12; furthermore, they showed that the gene is on rat chromosome 6 and that both are in close proximity to the Igh locus.

ANIMAL MODEL

Holland et al. (2000) transferred, in a tissue-specific manner, genes encoding activated forms of Ras (190070) and Akt to astrocytes and neural progenitors in mice. Holland et al. (2000) found that although neither activated Ras nor Akt alone was sufficient to induce glioblastoma multiforme (GBM; 137800) formation, the combination of activated Ras and Akt induced high-grade gliomas with the histologic features of human GBMs. These tumors appeared to arise after gene transfer to neural progenitors, but not after transfer to differentiated astrocytes. Increased activity of RAS is found in many human GBMs, and Holland et al. (2000) demonstrated that Akt activity is increased in most of these tumors, implying that combined activation of these 2 pathways accurately models the biology of this disease.

By targeted disruption of the Akt1 gene, Chen et al. (2001) created an Akt1-null mouse model. Homozygous mice were viable but smaller than wildtype littermates, and they did not display a diabetic phenotype. Upon exposure to genotoxic stress, their life span was shorter. Chen et al. (2001) found that the Akt1-null mice showed increased spontaneous apoptosis in testes and thymi. They observed an attenuation of spermatogenesis in the Akt1-null male mice, and thymocytes were more sensitive to gamma irradiation and dexamethasone-induced apoptosis. Akt1-null mouse embryo fibroblasts were also more susceptible to apoptosis induced by TNF, anti-Fas (134637), ultraviolet irradiation, and serum withdrawal.

To determine the effects of AKT on cardiac function in vivo, Condorelli et al. (2002) generated a mouse model of cardiac-specific Akt overexpression. Transgenic mice were generated by using the E40K, constitutively active mutant of Akt linked to the rat alpha-myosin heavy chain promoter (160710). The effects of cardiac-selective Akt overexpression were studied by echocardiography, cardiac catheterization, and histologic and biochemical techniques. Akt overexpression produced cardiac hypertrophy at the molecular and histologic levels, with a significant increase in cardiomyocyte cell size and concentric left ventricular hypertrophy. Akt-transgenic mice also showed a remarkable increase in cardiac contractility compared with wildtype controls as demonstrated in an invasive hemodynamic study. Diastolic function was not affected at rest but was impaired during graded dobutamine infusion. Other studies indicated that Akt induced hypertrophy in vivo by activating the GSK3B/GATA4 (600576) pathway. These results demonstrated that Akt regulates cardiomyocyte cell size in vivo and that Akt modulates cardiac contractility in vivo without directly affecting beta-adrenergic receptor (see 109630) signaling capacity.

Kim et al. (2003) found that, in addition to hypertrophy, transgenic mice with cardiac-specific overexpression of active Akt showed enhanced left ventricular function. Isolated ventricular myocytes showed increased contractility, which was associated with increased Ca(2+) transients and Ca(2+) channel currents. The rate of relaxation was also enhanced. Kim et al. (2003) determined that Serca2a protein levels were increased by 6.6-fold in transgenic animals, and inhibitor studies suggested that Serca2a overexpression mediated the enhanced left ventricular function.

Peng et al. (2003) developed Akt1/Akt2 double-knockout (DKO) mice. DKO mice showed severe growth deficiency and died shortly after birth. These mice displayed impaired skin development due to a proliferation defect, skeletal muscle atrophy due to marked decrease in individual muscle cell size, and impaired bone development. The defects were similar to the phenotype of Igf1 receptor (IGF1R; 147370)-deficient mice, suggesting that Akt may serve as an important downstream effector of Igf1r during mouse development. DKO mice also displayed impeded adipogenesis through decreased induction of Pparg (601487).

Using adenoviral vectors, Iaccarino et al. (2004) selectively transferred the human AKT1 gene to the common carotid endothelium of normotensive and spontaneously hypertensive rats (SHR). In vitro, the endothelial vasorelaxation response to acetylcholine, isoproterenol, and insulin was blunted in control carotids from SHR compared to normotensive rats, and human AKT1 overexpression corrected those responses. Blood flow assessed in vivo by Doppler ultrasound was reduced in SHR compared to normotensive rat carotids and normalized after AKT1 gene transfer. In primary cultured endothelial cells, there was mislocalization of AKT1 in SHR. Iaccarino et al. (2004) concluded that AKT1 plays a role in endothelial dysfunction in hypertension, and suggested that impaired membrane localization may be the pathogenic mechanism.

Ackah et al. (2005) found that loss of Akt1, but not Akt2, resulted in defective ischemia and Vegf-induced angiogenesis and severe peripheral vascular disease in mice. Akt1-knockout mice also had reduced endothelial progenitor cell (EPC) mobilization in response to ischemia. Introduction of EPCs from wildtype mice, but not EPCs from Akt1 -/- mice, into wildtype mice improved limb blood flow after ischemia. Loss of Akt1 reduced basal phosphorylation of several Akt substrates, migration of fibroblasts and endothelial cells, and nitric oxide release. Ackah et al. (2005) concluded that AKT1 exerts an essential role in blood flow control, cellular migration, and nitric oxide synthesis during postnatal angiogenesis.

Liu et al. (2005) presented evidence suggesting a role for G protein-coupled receptor kinase-2 (GRK2; 109635) in hepatic vascular dynamics in a rat model of liver sinusoidal endothelial injury and portal hypertension induced by bile duct ligation. Sinusoidal endothelial cells isolated from the affected animals had increased levels of GRK2, reduced levels of phosphorylated AKT and eNOS, and decreased levels of the vasodilator NO. Further analysis showed that the C terminus of GRK2 bound to and inhibited the phosphorylation and activation of AKT. Gene silencing of GRK2 using siRNA in injured sinusoidal endothelial cells restored AKT activity and resulted in increased NO production. Liu et al. (2005) also found that heterozygous Grk2 mice had increased levels of phosphorylated Akt and decreased portal hypertension in response to injury compared to wildtype mice. Liu et al. (2005) proposed a mechanism in which upregulation of GRK2 after endothelial cell injury directly inhibits phosphorylation of AKT, leading to reduced activation of eNOS and decreased production of NO, and resulting in portal hypertension.

Chen et al. (2005) demonstrated in mice that Akt1 is the predominant isoform in vascular endothelial cells. In vitro endothelial cells from Akt1-null mice showed impaired migration in response to VEGF and bound 3 times less fibrinogen (see 134820) than wildtype cells. Akt1-null mice showed significantly enhanced angiogenesis, which was associated with impaired blood vessel maturation and increased vascular permeability. The neovasculature in Akt1-null mice had decreased basement membrane thickness and decreased laminin (see 156225) deposition. These changes were associated with reduced expression of thrombospondin-1 (THBS1; 188060) and -2 (THBS2; 188061). Chen et al. (2005) concluded that Akt1 is vital for the regulation of vascular permeability, angiogenic responses, and vascular maturation.

Chen et al. (2006) demonstrated that Akt1 deficiency attenuated tumor development in Pten +/- mice.

Using gene expression profiling, Lai et al. (2006) found that Akt1-deficient mice showed alterations in the expression of genes in the prefrontal cortex involved in synaptic function, neuronal development, myelination, and actin polymerization. Although there was no detectable difference in expression of key dopamine-related genes, there was a trend for an increase in extracellular dopamine in the prefrontal cortex. Ultrastructural analysis showed changed in the dendritic architecture of pyramidal neurons in the prefrontal cortex. Akt1-deficient mice had normal acquisition of prefrontal cortex-dependent cognitive tasks but abnormal working memory retention under neurochemical challenge. Lai et al. (2006) suggested that the changes observed in Akt1-deficient mice may offer insight into changes observed in patients with schizophrenia.

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CONTRIBUTORS

Cassandra L. Kniffin - updated : 1/4/2007
Ada Hamosh - updated : 7/24/2006
Patricia A. Hartz - updated : 7/17/2006
Ada Hamosh - updated : 2/10/2006
Marla J. F. O'Neill - updated : 2/3/2006
Cassandra L. Kniffin - updated : 11/11/2005
Ada Hamosh - updated : 10/25/2005
Cassandra L. Kniffin - updated : 10/7/2005
Patricia A. Hartz - updated : 9/28/2005
Patricia A. Hartz - updated : 9/8/2005
Paul J. Converse - updated : 5/13/2004
Stylianos E. Antonarakis - updated : 4/30/2004
Ada Hamosh - updated : 4/7/2004
Patricia A. Hartz - updated : 2/17/2004
Victor A. McKusick - updated : 1/23/2004
Ada Hamosh - updated : 8/26/2003
Patricia A. Hartz - updated : 7/8/2003
Ada Hamosh - updated : 11/18/2002
Patricia A. Hartz - updated : 11/7/2002
Victor A. McKusick - updated : 10/21/2002
Stylianos E. Antonarakis - updated : 9/18/2002
Patricia A. Hartz - reorganized : 8/20/2002
Patricia A. Hartz - updated : 8/20/2002
Stylianos E. Antonarakis - updated : 11/6/2001
George E. Tiller - updated : 4/18/2001
Ada Hamosh - updated : 4/28/2000
Paul J. Converse - updated : 3/7/2000
Ada Hamosh - updated : 6/23/1999
Ada Hamosh - updated : 4/8/1999
Stylianos E. Antonarakis - updated : 4/1/1999

CREATION DATE

Victor A. McKusick : 6/2/1986

EDIT HISTORY

wwang : 1/26/2007
ckniffin : 1/4/2007
alopez : 9/19/2006
alopez : 7/27/2006
terry : 7/24/2006
mgross : 7/19/2006
terry : 7/17/2006
carol : 3/10/2006
alopez : 2/21/2006
terry : 2/10/2006
wwang : 2/3/2006
wwang : 2/1/2006
ckniffin : 11/11/2005
alopez : 10/26/2005
terry : 10/25/2005
carol : 10/11/2005
ckniffin : 10/7/2005
mgross : 10/7/2005
mgross : 10/6/2005
terry : 9/28/2005
mgross : 9/8/2005
terry : 3/16/2005
mgross : 9/23/2004
alopez : 6/9/2004
mgross : 5/13/2004
carol : 5/12/2004
mgross : 4/30/2004
alopez : 4/8/2004
alopez : 4/8/2004
terry : 4/7/2004
cwells : 2/23/2004
terry : 2/17/2004
alopez : 1/29/2004
terry : 1/23/2004
alopez : 9/2/2003
alopez : 8/26/2003
terry : 8/26/2003
mgross : 7/8/2003
cwells : 11/19/2002
terry : 11/18/2002
tkritzer : 11/14/2002
tkritzer : 11/7/2002
tkritzer : 11/7/2002
carol : 10/24/2002
tkritzer : 10/21/2002
tkritzer : 10/21/2002
mgross : 9/18/2002
mgross : 8/20/2002
mgross : 8/20/2002
mgross : 8/20/2002
mgross : 11/6/2001
mgross : 11/6/2001
cwells : 5/3/2001
cwells : 4/26/2001
cwells : 4/20/2001
cwells : 4/18/2001
alopez : 10/20/2000
alopez : 5/1/2000
terry : 4/28/2000
carol : 3/7/2000
alopez : 3/3/2000
alopez : 6/23/1999
alopez : 6/23/1999
alopez : 4/9/1999
alopez : 4/8/1999
mgross : 4/1/1999
psherman : 3/18/1999
mark : 1/30/1997
terry : 1/29/1997
mark : 5/9/1996
terry : 7/10/1995
mark : 6/19/1995
carol : 11/12/1993
carol : 5/7/1993
carol : 4/27/1993
carol : 11/6/1992

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