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)

Glial cell line derived neurotrophic factor (GDNF) signals through a multicomponent receptor complex consisting of RET receptor tyrosine kinase and a member of GDNF family receptor alpha (GFRalpha). Recently, it was shown that tyrosine 1062 in RET represents a binding site for SHC adaptor proteins and is crucial for both RAS/mitogen activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3-K)/AKT signaling pathways. In the present study, we characterized how these two pathways diverge from tyrosine 1062, using human neuroblastoma and primitive neuroectodermal tumor cell lines expressing RET at high levels. In response to GDNF stimulation, SHC bound to GAB1 and GRB2 adaptor proteins as well as RET, and SHC and GAB1 were highly phosphorylated on tyrosine. The complex formation consisting of SHC, GAB1 and GRB2 was almost abolished by replacement of tyrosine 1062 in RET with phenylalanine. Tyrosine-phosphorylated GAB1 was also associated with p85 subunit of PI3-K, resulting in PI3-K and AKT activation, whereas SHC-GRB2-SOS complex was responsible for the RAS/ERK signaling pathway. These results suggested that the RAS and PI3-K pathways activated by GDNF bifurcate mainly through SHC bound to tyrosine 1062 in RET. Furthermore, using luciferase reporter-gene assays, we found that the RAS/ERK and PI3-K signaling pathways are important for activation of CREB and NF-kappaB in GDNF-treated cells, respectively. Oncogene (2000) 19, 4469 - 4475.
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PMID:Characterization of intracellular signals via tyrosine 1062 in RET activated by glial cell line-derived neurotrophic factor. 1100 19

The addition of low concentrations (0.1-1 nM) of extracellular HIV-1 Tat protein to PC12 neuronal cells stimulated a rapid (peak at 5 min) elevation of the cAMP intracellular levels, which in turn induced the phosphorylation of CREB transcription factor (peak at 15 min) on serine-133 (Ser-133). On the contrary, at later time points (60-120 min) Tat induced a significant decline of intracellular cAMP with respect to the basal levels observed in control cells treated with bovine serum albumin. In blocking experiments performed with pharmacological inhibitors, Tat decreased the intracellular levels of cAMP and CREB Ser-133 phosphorylation through a signal transduction pathway involving the sequential activation of phosphatidylinositol 3-kinase, AKT, and cyclic nucleoside phosphodiesterases. Moreover, in transient transfection experiments, Tat inhibited transcription of CREB promoter in a manner strictly dependent on the presence of the cAMP-responsive elements (CRE) in the CREB promoter. Consistently, the expression of endogenous CREB protein was significantly reduced in PC12 cells by prolonged (24-48 h) treatment with Tat. This decline in the expression of CREB, which plays an essential role in the survival and function of neuronal cells, anticipated a progressive increase of apoptosis in Tat-treated cells. Although obtained in a neuronal cell line, our findings might help to explain some aspects of the pathogenesis of HIV-1-associated dementia.
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PMID:HIV-1 Tat protein down-regulates CREB transcription factor expression in PC12 neuronal cells through a phosphatidylinositol 3-kinase/AKT/cyclic nucleoside phosphodiesterase pathway. 1115 64

Glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) are two homologeous proteins that have been recognized as potent survival factors for distinct neuronal populations. GDNF and NTN act through a two-component receptor system consisting of the ligand-specific binding subunits GDNF family receptor (GFR)alpha-1 and GFRalpha-2 and the common transducing subunit c-Ret. In addition, it has been demonstrated that GDNF can signal through GFRalpha-1 in the absence of c-Ret. In the present study, we sought to determine whether a similar c-Ret-independent signaling applies for GFRalpha-2. In addition, we have characterized the ligand specificity of the c-Ret-independent action of GFRalphas. To establish an assay system for these studies, several neural cell lines were screened for the presence of GDNF and NTN receptor subunits by RT-PCR and immunoblot analysis. c-Ret expression was detectable only in Neuro2A cells, which did not express GFRalpha-1 or GFRalpha-2. The neuronal cell line LS expressed GFRalpha-2, and the glial cell line Mes42 expressed GFRalpha-1, whereas the neuronal cell line B104 expressed both GFRalpha-1 and GFRalpha-2. Stimulation of B104 and Mes42 cells with GDNF, but not with NTN, for 10 min resulted in CREB phosphorylation. In apparent contrast, neither NTN nor GDNF promoted CREB activation in LS and Neuro2A cells. Moreover, exposure of LS cells to NTN or GDNF also failed to activate AKT and ERK. Together these findings provide evidence that, in contrast to GFRalpha-1, GFRalpha-2 fails to signal in the absence of c-Ret. In addition, these observations reveal that c-Ret-independent signaling of GFRalpha-1 is ligand- specific and occurs only with GDNF.
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PMID:Evidence for a ligand-specific signaling through GFRalpha-1, but not GFRalpha-2, in the absence of Ret. 1174 56

The SGK1 protein belongs to the AGC gene family of kinases that are regulated by phosphorylation mediated by PDK1. SGK1 regulation is accomplished by several pathways including growth-factor and stress-mediated signaling. We have expanded the analysis of SGK1 regulation in epithelial cells. We used HA-tagged SGK1 to transiently transfect MDCK cells and study the regulation of SGK1 upon stimulation with HGF, cAMP or upon adhesion of the cells to immobilized fibronectin. In addition, we studied the regulation of SGK1 activity by small GTP-binding proteins of the Rho family. Treatment of MDCK cells with HGF leads to a time-dependent activation of SGK1 that is blocked by wortmanin. This activation requires the conserved phosphorylation site present in the activation loop of the kinase (T256 in SGK1) and the phosphorylation site present in a hydrophobic domain at its C-terminus (S422 in SGK1), which are targets for PDK1/PDK2-mediated regulation of SGK1. We tested whether SGK1 could be activated by cAMP as it contains a putative PKA site. We were unable to demonstrate a significant activation of HA-SGK1 by cAMP stimulation under conditions where we detect cAMP-mediated phosphorylation of the transcription factor CREB. Cotransfection of SGK1 with activated small GTP-binding proteins revealed that Rac1, but not Rho or Rap1, induces activation of SGK1. However, this activation was wortmanin insensitive and dominant-negative Rac1 did not inhibit the HGF-mediated activation of SGK1. Adhesion of MDCK cells to immobilized fibronectin also leads to activation of SGK1. However, it appears that the integrin-mediated activation of HA-SGK1 differs from AKT activation in the fact that AKT phosphorylation was blocked by wortmanin (or LY294002) whereas HA-SGK1 was not. The adhesion-dependent activation, however, requires the intact phosphorylation sites of SGK1. Co-transfection of HA-SGK1 with RacV12 results in increased activity in adherent cells compared with HA-SGK1 alone. Since RacN17 failed to inhibit adhesion dependent-activation of SGK1, it suggests that integrin activation is achieved by a parallel Rac-independent pathway. The activation of SGK1 by HGF and integrin provides a link between HGF-mediated protection of MDCK from de-attachment induced apoptosis (anoikis). We demonstrate that dephosphorylation of the transcription factor FKRHL1 induced by cell de-attachment is prevented by activated SGK1, suggesting that SGK1 regulates cell survival pathways. In summary, we demonstrate that SGK1 activation could be achieved through signaling pathways involved in the regulation of cell survival, cell-cell and cell-matrix interactions. SGK1 activation can be accomplished via HGF, PI-3K-dependent pathways and by integrin-mediated, PI-3K independent pathways. In addition, activation of SGK1 by the small GTP-binding protein Rac1 has been observed.
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PMID:Activation of SGK1 by HGF, Rac1 and integrin-mediated cell adhesion in MDCK cells: PI-3K-dependent and -independent pathways. 1195 29

Given that brain-derived neutrophic factor (BDNF) modulates both short-term synaptic function and activity-dependent synaptic plasticity in the adult hippocampus, here we examined signaling mechanisms in vivo in the hippocampus mediating BDNF modulation of long-term memory (LTM) formation of a one-trial fear-motivated learning task in rats. Bilateral infusions of function-blocking anti-BDNF antibody into the CA1 region of the dorsal hippocampus decreased extracellular-signal regulated kinase 2 (ERK2) and CREB activation and impaired LTM retention scores. Inhibition of ERK1/2 activation by PD098059 produced similar effects and also reduced CREB phosphorylation. In contrast, intrahippocampal administration of recombinant human BDNF increased ERK1/2 and CREB activation and facilitated LTM. Activated-p38, activated-PKC isoforms, and activated-AKT were unaltered after BDNF or anti-BDNF infusion. In addition, no changes were found on alphaPKA and betaPKA catalytic subunits in nuclear samples. Thus, our results suggest that BDNF exerts its role in LTM formation in vivo in CA1 region of the hippocampus, at least in part, via CREB activation. Moreover, BDNF-induced CREB activation appears to be mediated mainly through the activation of ERK1/2 signaling pathway.
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PMID:Signaling mechanisms mediating BDNF modulation of memory formation in vivo in the hippocampus. 1258 86

15-deoxy-Delta(12,14) prostaglandin J(2) (15dPGJ(2)), a peroxisome proliferator-activated receptor gamma (PPARgamma) ligand, induced synergistic stimulation of DNA synthesis in the presence of phorbol dibutyrate (PDB) in Swiss 3T3 cells. This effect was dose-dependent and the maximum response was obtained at 2 microM 15dPGJ(2), although higher concentrations of 15dPGJ(2) were cytotoxic. Furthermore, 15dPGJ(2) synergizes with PDB to induce cell-cycle progression and cyclin D(1) expression. Rosiglitazone and ciglitazone, two other agonists of PPARgamma, did not synergize with PDB to induce DNA synthesis, suggesting that activation of PPARgamma is not involved in 15dPGJ(2)-induced DNA synthesis. 15dPGJ(2) neither increased the levels of cAMP, nor changed the phosphorylation state of CREB, nor induced calcium mobilization, indicating that 15dPGJ(2) effects are independent of prostaglandin D(2) receptor (DP1 and DP2). Moreover, 15dPGJ(2) did not induce activation of PKB/AKT or activation of extracellular signal-regulated kinase (ERK). These results establish a proliferative role for 15dPGJ(2) in Swiss 3T3 cells independent of the activation of PPARgamma or the PGD(2) receptors.
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PMID:15-deoxy-delta12,14 prostaglandin J2 synergizes with phorbol ester to induce proliferation in Swiss 3T3 cells independently of peroxisome proliferator-activated receptor gamma and PGD2 receptors. 1270 51

TSH activates its specific receptor in thyroid cells and induces cAMP, a robust stimulator of thyroid cell proliferation. Conversely, cAMP is a potent inhibitor of growth in mouse fibroblasts. To dissect the signals mediating cAMP-dependent growth, we have expressed in mouse fibroblasts the human thyrotropin receptor (TSHR) or a constitutively active mutant, under the control of the tetracyclin promoter. Both TSHR and cAMP levels were modulated by tetracyclin. In the presence of serum, activation of TSHR by TSH induced growth arrest. In the absence of serum, cells expressing TSHR stimulated with TSH, replicated their DNA, but underwent apoptosis. Co-expression of cAMP-dependent protein kinase (PKA) regulatory subunit type II (RIIbeta) inhibited apoptosis and stimulated the growth of cells only in the presence of TSH. Expression of RIIbeta-PKA, in the absence of TSHR, induced apoptosis, which was reversed by cAMP. Growth, stimulated by TSHR-RIIbeta-PKA in mouse fibroblasts, was also dependent on Rap1 activity, indicating cAMP-dependent growth in thyroid cells. As for the molecular mechanism underlying these effects, we found that in normal fibroblasts, TSH induced AKT and ERK1/2 only in cells expressing TSHR and RII. Similarly, activation of TSHR increased cAMP levels greatly, but was unable to stimulate CREB phosphorylation and transcription of cAMP-induced genes in the absence of RII. These data provide a simple explanation for the anti-proliferative and proliferative effects of cAMP in different cell types and indicate that RII-PKAII complements TSHR action by stably propagating robust cAMP signals in cell compartments.
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PMID:The expression of the thyroid-stimulating hormone (TSH) receptor and the cAMP-dependent protein kinase RII beta regulatory subunit confers TSH-cAMP-dependent growth to mouse fibroblasts. 1290 33

In vivo, left ventricular remodeling after myocardial infarction involves hypertrophy generally attributed to increased cardiac workload. We hypothesized that hypoxia/reoxygenation directly induces cardiomyocyte hypertrophy and studied several participating kinases and transcription factors in isolated cardiomyocytes. Hypoxia for 6 h followed by 42 h reoxygenation induced cardiomyocyte hypertrophy assessed by 3H leucine incorporation and immunohistochemistry. Inhibition of reactive oxygen species (ROS), serine/threonine kinase AKT, and ERK abolished reoxygenation-induced hypertrophy. In addition, a beta2-adrenergic receptor (beta2-AR) antagonist, as well as Gi inhibitor pertussis toxin, blocked reoxygenation-induced hypertrophy. Hypoxia for 6 h increased transcription factors CREB, NF-kappaB, and GATA DNA binding activities. However, only CREB DNA-binding was sustained during reoxygenation. Inhibition of PI3-kinase, ERK, and PKA abrogated reoxygenation-induced CREB DNA-binding without affecting CREB serine-133 phosphorylation. These same pathways were found to regulate hypoxia/reoxygenation-induced GSK3beta kinase activity and CREB serine-129 de-phosphorylation. GSK3beta mutants resistant to phosphorylation blocked the stimulation of CRE-dependent transcription induced by hypoxia/reoxygenation. Transfection of cardiomyocytes with a dominant-negative mutant of CREB abrogated hypoxia/reoxygenation-induced hypertrophy. We suggest that hypoxia/reoxygenation induces cardiomyocyte hypertrophy through CREB activation. Inactivation of GSK3beta by hypoxia/reoxygenation, possibly integrating PI3-kinase and ERK pathways downstream of beta2-AR and ROS, is a prerequisite for CRE-dependent transcription. Transient hypoxia may contribute to cardiac hypertrophy in ischemic heart disease independent of cardiac workload.
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PMID:Reoxygenation after severe hypoxia induces cardiomyocyte hypertrophy in vitro: activation of CREB downstream of GSK3beta. 1515 64

Radiation exposure is known to have profound effects on the brain, leading to precursor cell dysfunction and debilitating cognitive declines [Nat. Med. 8 (2002) 955]. Although a plethora of data exist on the effects of high radiation doses, the effects of low-dose irradiation, such as ones received during repetitive diagnostic and therapeutic exposures, are still under-investigated [Am. J. Otolaryngol. 23 (2002) 215; Proc. Natl. Acad. Sci. USA 97 (2000) 889; Curr. Opin. Neurol. 16 (2003) 129]. Furthermore, most studies of the biological effects of ionizing radiation have been performed using a single acute dose, while clinically and environmentally relevant exposures occur predominantly under chronic/repetitive conditions. Here, we have used a mouse model to compare the effects of chronic/repetitive and acute low-dose radiation (LDR) exposure (0.5Gy) to ionizing radiation on the brain in vivo. We examined the LDR effects on p42/44 MAPK (ERK1/ERK2), CaMKII, and AKT signaling-the interconnected pathways that have been previously shown to be crucial for neuronal survival upon irradiation. We report perturbations in ERK1/2, AKT, and CREB upon acute and chronic/repetitive low-dose exposure in the hippocampus and frontal cortex of mice. These studies were paralleled by the analysis of radiation effects on neurogenesis and cellular proliferation. Repetitive exposure had a much more pronounced effect on cellular signaling and neurogenesis than acute exposure. These results suggest that studies of single acute exposures might be limited in terms of their predictive value. We also present the first evidence of sex differences in radiation-induced signaling in the hippocampus and frontal cortex. We show the role of estrogens in brain radiation responses and discuss the implications of the observed changes.
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PMID:Selective brain responses to acute and chronic low-dose X-ray irradiation in males and females. 1555 57

Protein kinase B, also known as Akt, is a serine/threonine kinase and plays a critical role in the modulation of cell development, growth, and survival. Interestingly, Akt is ubiquitously expressed throughout the body, but its expression in the nervous system is substantially up-regulated during cellular stress, suggesting a more expansive role for Akt in the nervous system that may involve cellular protection. In this regard, a body of recent work has identified a robust capacity for Akt and its downstream substrates to foster both neuronal and vascular survival during apoptotic injury. Cell survival by Akt is driven by the modulation of both intrinsic cellular pathways that oversee genomic DNA integrity and extrinsic mechanisms that control inflammatory microglial activation. A series of distinct pathways are regulated by Akt that include the Forkhead family of transcription factors, GSK-3 beta, beta-catenin, c-Jun, CREB, Bad, IKK, and p53. Culminating below these substrates of Akt are the control of caspase mediated pathways that promote genomic integrity as well as prevent inflammatory cell demise. With further levels of progress in defining the cellular role of Akt, the attractiveness of Akt as a vital and broad cytoprotectant for both neuronal and vascular cell populations should continue to escalate.
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PMID:Activating Akt and the brain's resources to drive cellular survival and prevent inflammatory injury. 1557 47


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