Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P31749 (AKT)
 22,954 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In Caenorhabditis elegans, an insulin-like signaling pathway to phosphatidylinositol 3-kinase (PI 3-kinase) and AKT negatively regulates the activity of DAF-16, a Forkhead transcription factor. We show that in mammalian cells, C. elegans DAF-16 is a direct target of AKT and that AKT phosphorylation generates 14-3-3 binding sites and regulates the nuclear/cytoplasmic distribution of DAF-16 as previously shown for its mammalian homologs FKHR and FKHRL1. In vitro, interaction of AKT- phosphorylated DAF-16 with 14-3-3 prevents DAF-16 binding to its target site in the insulin-like growth factor binding protein-1 gene, the insulin response element. In HepG2 cells, insulin signaling to PI 3-kinase/AKT inhibits the ability of a GAL4 DNA binding domain/DAF-16 fusion protein to activate transcription via the insulin-like growth factor binding protein-1-insulin response element, but not the GAL4 DNA binding site, which suggests that insulin inhibits the interaction of DAF-16 with its cognate DNA site. Elimination of the DAF-16/1433 association by mutation of the AKT/14-3-3 sites in DAF-16, prevents 14-3-3 inhibition of DAF-16 DNA binding and insulin inhibition of DAF-16 function. Similarly, inhibition of the DAF-16/14-3-3 association by exposure of cells to the PI 3-kinase inhibitor LY294002, enhances DAF-16 DNA binding and transcription activity. Surprisingly constitutively nuclear DAF-16 mutants that lack AKT/14-3-3 binding sites also show enhanced DNA binding and transcription activity in response to LY294002, pointing to a 14-3-3-independent mode of regulation. Thus, our results demonstrate at least two mechanisms, one 14-3-3-dependent and the other 14-3-3-independent, whereby PI 3-kinase signaling regulates DAF-16 DNA binding and transcription function.
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PMID:Phosphatidylinositol 3-kinase signaling inhibits DAF-16 DNA binding and function via 14-3-3-dependent and 14-3-3-independent pathways. 1112 66

C. elegans insulin-like signaling regulates metabolism, development, and life span. This signaling pathway negatively regulates the activity of the forkhead transcription factor DAF-16. daf-16 encodes multiple isoforms that are expressed in distinct tissue types and are probable orthologs of human FKHRL1, FKHR, and AFX. We show that human FKHRL1 can partially replace DAF-16, proving the orthology. In mammalian cells, insulin and insulin-like growth factor signaling activate AKT/PKB kinase to negatively regulate the nuclear localization of DAF-16 homologs (reviewed in ). We show that the absence of AKT consensus sites on DAF-16 is sufficient to cause dauer arrest in daf-2(+) animals, proving that daf-16 is the major output of insulin signaling in C. elegans. FKHR, FKRHL1, and AFX may similarly be the major outputs of mammalian insulin signaling. daf-2 insulin signaling, via AKT kinases, negatively regulates DAF-16 by controlling its nuclear localization. Surprisingly, we find that daf-7 TGF-beta signaling also regulates DAF-16 nuclear localization specifically at the time when the animal makes the commitment between diapause and reproductive development. daf-16 function is supported by the combined action of two distinct promoter/enhancer elements, whereas the coding sequences of two major DAF-16 isoforms are interchangeable. Together, these observations suggest that the combined effects of transcriptional and posttranslational regulation of daf-16 transduce insulin-like signals in C. elegans and perhaps more generally.
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PMID:Regulation of C. elegans DAF-16 and its human ortholog FKHRL1 by the daf-2 insulin-like signaling pathway. 1174 21

Cerebellar granule neurons depend on insulin-like growth factor-I (IGF-I) for their survival. However, the mechanism underlying the neuroprotective effects of IGF-I is presently unclear. Here we show that IGF-I protects granule neurons by suppressing key elements of the intrinsic (mitochondrial) death pathway. IGF-I blocked activation of the executioner caspase-3 and the intrinsic initiator caspase-9 in primary cerebellar granule neurons deprived of serum and depolarizing potassium. IGF-I inhibited cytochrome c release from mitochondria and prevented its redistribution to neuronal processes. The effects of IGF-I on cytochrome c release were not mediated by blockade of the mitochondrial permeability transition pore, because IGF-I failed to inhibit mitochondrial swelling or depolarization. In contrast, IGF-I blocked induction of the BH3-only Bcl-2 family member, Bim (Bcl-2 interacting mediator of cell death), a mediator of Bax-dependent cytochrome c release. The suppression of Bim expression by IGF-I did not involve inhibition of the c-Jun transcription factor. Instead, IGF-I prevented activation of the forkhead family member, FKHRL1, another transcriptional regulator of Bim. Finally, adenoviral-mediated expression of dominant-negative AKT activated FKHRL1 and induced expression of Bim. These data suggest that IGF-I signaling via AKT promotes survival of cerebellar granule neurons by blocking the FKHRL1-dependent transcription of Bim, a principal effector of the intrinsic death-signaling cascade.
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PMID:Insulin-like growth factor-I blocks Bcl-2 interacting mediator of cell death (Bim) induction and intrinsic death signaling in cerebellar granule neurons. 1241 54

Intermittent hypoxia (IH) during sleep induces temporally defined increases in apoptosis within vulnerable brain regions such as the hippocampal CA1 region in rats. Protein kinase B (AKT) has emerged as major signal transduction protein underlying inhibition of apoptosis and consequent increases in cell survival. Sprague Dawley adult male rats were exposed during sleep to IH or to normoxia (RA) for periods ranging from 0 to 30 days, and expression of total and phosphorylated AKT, of forkhead family members FKHR and FKHRL1, and of glycogen synthase kinase 3beta (GSK3beta) was assessed. Decreases in phosphorylation occurred as early as 1 h IH exposure, reached a nadir at 6 h-3 days, and then progressively returned to baseline levels at 14-30 days. Phosphorylated AKT and GSK3beta were intensely expressed and highly colocalized within neuronal cells (Neu-N positive) in the CA1 region. Thus, IH induces time-dependent biphasic changes in AKT survival pathways within the CA1 region that are temporally correlated with the initial increases and subsequent decreases in neuronal apoptosis.
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PMID:Intermittent hypoxia induces time-dependent changes in the protein kinase B signaling pathway in the hippocampal CA1 region of the rat. 1467 60

The DAF-2 insulin receptor-like signaling pathway controls metabolism, development, longevity, and stress response in C. elegans. Here we show that SGK-1, the C. elegans homolog of the serum- and glucocorticoid-inducible kinase SGK, acts in parallel to the AKT kinases to mediate DAF-2 signaling. Loss of sgk-1 results in defective egg-laying, extended generation time, increased stress resistance, and an extension of life span. SGK-1 forms a protein complex with the AKT kinases, and is activated by and strictly depends on PDK-1. All three kinases of this complex are able to directly phosphorylate DAF-16/FKHRL1, yet have different functions in DAF-2 signaling. Whereas AKT-1 and AKT-2 are more important for regulating dauer formation, SGK-1 is the crucial factor for the control of development, stress response, and longevity. Our data also suggest the existence of a second pathway from DAF-2 to DAF-16 that does not depend on AKT-1, AKT-2, and SGK-1.
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PMID:C. elegans SGK-1 is the critical component in the Akt/PKB kinase complex to control stress response and life span. 1506 96

In this study, we have characterized the signaling pathways mediated by CXCR4 in breast cancer cells and its role in breast cancer cell invasion and migration. Stromal cell-derived factor 1alpha (SDF-1alpha; CXCL12) stimulation of breast cancer cells resulted in phosphoinositide 3-kinase (PI-3K) activation, AKT phosphorylation, and activation of the FKHRL1 transcription factor. In addition, SDF-1alpha induced activation of the focal adhesion kinase (FAK) as well as the migration of breast cancer cells. Expression of SDF-1alpha, the ligand of CXCR4, was about 2-fold higher in microdissected human breast epithelial cancer cells as compared with normal epithelial cells. Immunohistochemical analysis indicated that SDF-1alpha expression is consistently higher in primary breast tumor cells than in normal breast epithelial cells. Furthermore, SDF-1alpha induced blood vessel instability, through increased vascular permeability, resulting in the penetration of breast tumor cells through the human brain microvascular endothelial cells (HBMEC). Notably, the migration of breast cancer cells was inhibited by the PI-3K inhibitor, Wortmannin, and the Ca(2+) inhibitor BAPTA/AM, indicating that transendothelial breast cancer cell migration induced by SDF-1alpha is mediated by activation of the PI-3K/AKT pathway and Ca(2+)-mediated signaling. Blockade of the CXCR4/SDF1 signaling pathway with anti-CXCR4 antibody also decreased transendothelial breast cancer cell migration as well as vascular permeability. This study focuses on novel interactions between highly relevant signaling pathways in breast cancer cells and brain microvascular endothelial cells and may provide insights into the molecular mechanisms of CXCR4/SDF-1alpha-mediated breast cancer metastasis to the brain.
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PMID:Involvement of the chemokine receptor CXCR4 and its ligand stromal cell-derived factor 1alpha in breast cancer cell migration through human brain microvascular endothelial cells. 1523 8

The genetic mechanisms that control proliferation of childhood musculoskeletal malignancies, notably Ewing's tumor (ET) and rhabdomyosarcoma (RMS), remain largely unknown. Most human cancers appear to overexpress at least one of the G1 cyclins (cyclins D1, D2, D3, E1, and E2) to bypass normal regulation of cell cycle G1 progression. We compared the gene expression profiles of 7 ET and 13 RMS primary tumor samples and found overexpression of cyclin D1 in all 7 ET samples. In contrast, RMS samples expressed higher levels of cyclin D2, cyclin D3, and cyclin E1. This was confirmed by quantitative reverse transcription-polymerase chain reaction and Western blot. The relative roles of RAS-extracellular signal-regulated kinase 1/2 and phosphatidylinositol 3'-kinase (PI3K)-AKT pathways in the regulation of D-type cyclin expression in these tumors were then assessed. Inhibition of either pathway reduced expression of cyclins D1, D2, and D3 in RMS lines, whereas only PI3K inhibitors blocked cyclin D1, D2, and D3 expression in ET lines. Furthermore, PI3K-AKT appeared to regulate D-type cyclin transcription in RMS lines through FKHR and FKHRL1. Finally, the role of the ET-associated EWS-FLI1 fusion gene in regulating D cyclin expression was studied. Inhibition of EWS-FLI1 expression in the TC71 ET line decreased cyclin D1 levels but increased cyclin D3 levels. In contrast, induction of EWS-FLI1 expression in the RD RMS cell line increased cyclin D1 expression but decreased cyclin D3 expression. Our results demonstrate distinct regulation of D-type cyclins in ET and RMS and indicate that EWS-FLI1 can modulate the expression of D-type cyclins independent of cellular backgrounds.
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PMID:Selective usage of D-Type cyclins by Ewing's tumors and rhabdomyosarcomas. 1534 83

FKHRL1 (FOXO3a) and p53 are two potent stress-response regulators. Here we show that these two transcription factors exhibit "crosstalk" in vivo. In response to DNA damage, p53 activation led to FKHRL1 phosphorylation and subcellular localization change, which resulted in inhibition of FKHRL1 transcription activity. AKT was dispensable for p53-dependent suppression of FKHRL1. By contrast, serum- and glucocorticoid-inducible kinase 1 (SGK1) was significantly induced in a p53-dependent manner after DNA damage, and this induction was through extracellular signal-regulated kinase 1/2-mediated posttranslational regulation. Furthermore, inhibition of SGK1 expression by a small interfering RNA knockdown experiment significantly decreased FKHRL1 phosphorylation in response to DNA damage. Taken together, our observations reveal previously unrecognized crosstalk between p53 and FKHRL1. Moreover, our findings suggest a new pathway for understanding aging and the age dependency of human diseases governed by these two transcription factors.
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PMID:p53-dependent inhibition of FKHRL1 in response to DNA damage through protein kinase SGK1. 1538 58

PIK3CA is mutated in diverse human cancers, but the functional effects of these mutations have not been defined. To evaluate the consequences of PIK3CA alterations, the two most common mutations were inactivated by gene targeting in colorectal cancer (CRC) cells. Biochemical analyses of these cells showed that mutant PIK3CA selectively regulated the phosphorylation of AKT and the forkhead transcription factors FKHR and FKHRL1. PIK3CA mutations had little effect on growth under standard conditions, but reduced cellular dependence on growth factors. PIK3CA mutations resulted in attenuation of apoptosis and facilitated tumor invasion. Treatment with the PI3K inhibitor LY294002 abrogated PIK3CA signaling and preferentially inhibited growth of PIK3CA mutant cells. These data have important implications for therapy of cancers harboring PIK3CA alterations.
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PMID:Mutant PIK3CA promotes cell growth and invasion of human cancer cells. 1595 Sep 5

The GTPase-deficient, activated mutant of Galpha12 (Galpha12Q229L, or Galpha12QL) induces neoplastic growth and oncogenic transformation of NIH 3T3 cells. Using microarray analysis, we have previously identified a role for platelet-derived growth factor receptor alpha (PDGFRalpha) in Galpha12-mediated cell growth (R. N. Kumar et al., Cell Biochem. Biophys. 41:63-73, 2004). In the present study, we report that Galpha12QL stimulates the functional expression of PDGFRalpha and demonstrate that the expression of PDGFRalpha by Galpha12QL is dependent on the small GTPase Rho. Our results indicate that it is cell type independent as the transient expression of Galpha12QL or the activation of Galpha12-coupled receptors stimulates the expression of PDGFRalpha in NIH 3T3 as well as in human astrocytoma 1321N1 cells. Furthermore, we demonstrate the presence of an autocrine loop involving PDGF-A and PDGFRalpha in Galpha12QL-transformed cells. Analysis of the functional consequences of the Galpha12-PDGFRalpha signaling axis indicates that Galpha12 stimulates the phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway through PDGFR. In addition, we show that Galpha12QL stimulates the phosphorylation of forkhead transcription factor FKHRL1 via AKT in a PDGFRalpha- and PI3K-dependent manner. Since AKT promotes cell growth by blocking the transcription of antiproliferative genes through the inhibitory phosphorylation of forkhead transcription factors, our results describe for the first time a PDGFRalpha-dependent signaling pathway involving PI3K-AKT-FKHRL1, regulated by Galpha12QL in promoting cell growth. Consistent with this view, we demonstrate that the expression of a dominant negative mutant of PDGFRalpha attenuated Galpha12-mediated neoplastic transformation of NIH 3T3 cells.
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PMID:Transactivation of platelet-derived growth factor receptor alpha by the GTPase-deficient activated mutant of Galpha12. 1635 79


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