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

PTEN is a tumor suppressor gene located on chromosome 10q23 and is amongst the most commonly mutated genes in human cancers. The lipid phosphatase activity of Pten enables it to dephosphorylate PIP3, thereby antagonizing growth factor stimulated PI3-kinase signaling mediated by AKT/PKB. The growth inhibition effect of PTEN has been shown to be mediated by p27 which is one of the important effector molecules downstream of the AKT pathway. Recently the importance of the Pten and AKT pathway in the regulation of the immune system and development of hematological malignancies has been shown. Loss of Pten and p27 expressions were examined immunohistochemically in 45 patients with peripheral T- and NK-cell lymphoma. Partial or complete loss of Pten was detected in 66.7% of the cases of anaplastic large cell lymphoma (ALCL) compared to only 12.5% of all other mature T-/NK-cell lymphomas combined. Loss of p27 was identified in 64.9% of cases, which showed a positive correlation with Pten loss. In this study, we showed that loss of Pten is more frequent in ALCL as compared to other mature T-/NK-cell lymphomas, which strongly correlates with the loss of p27 expression. Our findings provide further evidence for the importance of the deregulation of the PI3K-AKT pathway in ALCL.
 ...
PMID:PTEN and p27 expression in mature T-cell and NK-cell neoplasms. 1619 92

Host defense against viruses probably depends on targeted death of infected host cells and then clearance of cellular corpses by macrophages. For this process to be effective, the macrophage must presumably avoid its own virus-induced death. Here we identify one such mechanism. We show that mice lacking the chemokine Ccl5 are immune compromised to the point of delayed viral clearance, excessive airway inflammation and respiratory death after mouse parainfluenza or human influenza virus infection. Virus-inducible levels of Ccl5 are required to prevent apoptosis of virus-infected mouse macrophages in vivo and mouse and human macrophages ex vivo. The protective effect of Ccl5 requires activation of the Ccr5 chemokine receptor and consequent bilateral activation of G(alphai)-PI3K-AKT and G(alphai)-MEK-ERK signaling pathways. The antiapoptotic action of chemokine signaling may therefore allow scavengers to finally stop the host cell-to-cell infectious process.
 ...
PMID:CCL5-CCR5 interaction provides antiapoptotic signals for macrophage survival during viral infection. 1620 18

Interleukin 2 (IL-2) and interleukin 15 (IL-15) bind to common T-cell surface receptors comprised of unique alpha (IL-2R alpha or IL-15R alpha) and shared beta/gamma chain subunits. Ligation of this receptor by IL-2 can lead to apoptosis whereas IL-15 ligation favors cell survival. Our study examined intra-cellular signaling events associated with IL-2- and IL-15-induced apoptosis and survival in human T cells. We found IL-2 and IL-15 could both induce apoptosis and survival; the outcome depended on cytokine concentration. No qualitative differences in Jak/Stat, Ras/MAPK or PI3K/AKT signaling were seen over a wide range of IL-2 and IL-15 concentrations. These findings suggest that, like T-cell receptor signaling, IL-2R beta/gamma chain signaling is regulated, or "tuned," by the concentration of cytokine.
 ...
PMID:Signaling T-cell survival and death by IL-2 and IL-15. 1621 21

Somatic mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene in lung cancers have generated enormous interest, because they predict for sensitivity to TK inhibitors (TKIs). While mutational status is of great importance in determining response to TKIs, it is not the sole factor, and evidence is accumulating that EGFR gene amplification, other members of the EGFR family (HER2, HER3) and genes downstream of EGFR signaling (KRAS, BRAF), may be involved in cancer pathogenesis and the response of TKIs. EGFR mutations occur in highly selected subpopulations of lung cancer patients: adenocarcinoma histology, never-smoker status, East Asian ethnicity and female gender. The recent finding of "a resistance associated" mutation for TKIs also provides new insights into this complicated mechanism. Thus, molecular-based studies to analyze the biological functions and to assess TKI sensitivity depending on the type of mutations are required. Epidemiological studies to identify possible carcinogenic factor(s) affecting different subpopulations are also of interest. In addition, for optimal therapeutic approach a comprehensive understanding of the genes related to EGFR signaling pathway, including RAS/RAF/MAPK and PI3K-AKT pathways, are required.
 ...
PMID:Somatic mutations of epidermal growth factor receptor signaling pathway in lung cancers. 1623 26

Elucidation of mechanisms by which receptor protein tyrosine phosphatases (PTPs) regulate neurite outgrowth will require characterization of ligand-receptor interactions and identification of ligand-induced signalling components mediating neurite outgrowth. The first identified ligand of the leucocyte common antigen-related (LAR) receptor PTP consists of a 99-residue ectodomain isoform, termed LARFN5C, which undergoes homophilic binding to LAR and promotes neurite outgrowth. We employed peptide mapping of LARFN5C to identify an active neurite-promoting domain of LAR. A peptide mimetic consisting of 37 residues (L59) and corresponding to the fifth LAR fibronectin type III (FNIII) domain prevented LARFN5C homophilic binding, demonstrated homophilic binding to itself and promoted neurite outgrowth of mouse E16-17 hippocampal neurons and of dorsal root ganglia explants. Response to L59 was partially lost when using neurons derived from LAR-deficient (-/-) mice or neurons treated with LAR siRNA, consistent with homophilic interaction of L59 with LAR. L59 neurite-promoting activity was decreased in the presence of inhibitors of Src, Trk, PLCgamma, PKC, PI3K and MAPK. L59 activated Src (a known substrate of LAR), FAK and TrkB and also activated downstream signalling intermediates including PKC, ERK, AKT and CREB. BDNF augmented the maximal neurite-promoting activity of L59, a finding consistent with the presence of shared and distinct signalling pathways activated by L59 with BDNF and L59 with TrkB. These studies are the first to identify an ectodomain of LAR (located within the fifth FNIII domain) capable of promoting neurite outgrowth and point to novel approaches for promotion of neurite outgrowth.
 ...
PMID:Identification of an ectodomain within the LAR protein tyrosine phosphatase receptor that binds homophilically and activates signalling pathways promoting neurite outgrowth. 1626 54

Mutations of RAS, RAF, and PTEN, all important members of the RAS/MAPK and PI3K/AKT cascades, are reported in a variety of human tumors, including melanomas and endometrial cancer. In endometrial cancer, mutually exclusive mutations of PTEN and KRAS have been reported. On the other hand, mutation of BRAF is highly frequent, and mutually exclusive mutations of BRAF and NRAS have also been reported in melanomas. In this study, we elucidated the involvement of the up-regulation of RAS/MAPK and PI3K/AKT cascades in the pathogenesis of endometrial cancer and melanoma by analyzing the genes and molecules in these cascades. Twelve cell lines, six melanoma and six endometrial cancer, were analyzed; 4 (67%) of the 6 melanomas had gene mutations in the RAS/MAPK cascade, and a decrease or loss of PTEN expression was also observed. These results suggested that simultaneous up-regulations in these two cascades play important roles in carcinogenesis of melanocytes. However, no activation of AKT by phosphorylation was observed. On the other hand, 4 (67%) of the 6 endometrial cancer cell lines had mutually exclusive up-regulations in these cascades. However, two cell lines with up-regulation of the PI3K/AKT cascade also had up-regulation in the RAS/MAPK cascade induced by inactivation of DUSP6. These results suggest that simultaneous up-regulation of RAS/MAPK and PI3K/AKT cascades are crucial events in the pathogenesis of melanocytes, whereas up-regulation of either the RAS/MAPK or PI3K/AKT cascade is crucial for the majority of endometrial cancers.
 ...
PMID:Exploration of genetic alterations in human endometrial cancer and melanoma: distinct tumorigenic pathways that share a frequent abnormal PI3K/AKT cascade. 1627 42

17beta-Estradiol (E2) acts as a chemical messenger in target tissues inducing both slow nuclear and rapid extra-nuclear responses. E2 binds to its cognate nuclear receptors (ER) resulting in the activation of target gene transcription in the nucleus. In addition to these genomic effects, E2 modulates cell functions through rapid non-genomic actions. Stimulation of G-proteins, Ca(2+) influx, inositol phosphate generation as well as phospholipase C, ERK/MAPK, and PI3K/AKT activation all occur within seconds to minutes after E2 binding to a small population of ERalpha located at the plasma membrane. The great impact of these rapid signals on cell physiology renders central the knowledge of the structural bases and mechanisms that mediate extra-nuclear signaling by E2. Several laboratories, including our own, have recently elucidated the structural requirements for localization and function of plasma membrane ERalpha. This review summarizes the molecular mechanisms of E2-induced rapid non-genomic actions relevant for cell functions, highlighting the role of lipid modification (i.e., palmitoylation) in the ERalpha localization to and residence at the plasma membrane.
 ...
PMID:S-palmitoylation modulates estrogen receptor alpha localization and functions. 1627 18

The hypoxia-inducible factor (HIF) is a heterodimeric transcription factor composed of a constitutively expressed HIF-beta subunit and an oxygen-regulated HIF-alpha subunit. We have previously defined a hypoxia-inducible transcriptional response in Drosophila melanogaster that is homologous to the mammalian HIF-dependent response. In Drosophila, the bHLH-PAS proteins Similar (Sima) and Tango (Tgo) are the functional homologues of the mammalian HIF-alpha and HIF-beta subunits, respectively. HIF-alpha/Sima is regulated by oxygen at several different levels that include protein stability and subcellular localization. We show here for the first time that insulin can activate HIF-dependent transcription, both in Drosophila S2 cells and in living Drosophila embryos. Using a pharmacological approach as well as RNA interference, we determined that the effect of insulin on HIF-dependent transcriptional induction is mediated by PI3K-AKT and TOR pathways. We demonstrate that stimulation of the transcriptional response involves upregulation of Sima protein but not sima mRNA. Finally, we have analyzed in vivo the effect of the activation of the PI3K-AKT pathway on the subcellular localization of Sima protein. Overexpression of dAKT and dPDK1 in normoxic embryos provoked a major increase in Sima nuclear localization, mimicking the effect of a hypoxic treatment. A similar increase in Sima nuclear localization was observed in dPTEN homozygous mutant embryos, confirming that activation of the PI3K-AKT pathway promotes nuclear accumulation of Sima protein. We conclude that regulation of HIF-alpha/Sima by the PI3K-AKT-TOR pathway is a major conserved mode of regulation of the HIF-dependent transcriptional response in Drosophila.
 ...
PMID:The insulin-PI3K/TOR pathway induces a HIF-dependent transcriptional response in Drosophila by promoting nuclear localization of HIF-alpha/Sima. 1627 94

While tumors become addicted to oncogenes like Ras, the microenvironment in which tumor cells reside changes during tumorigenesis; the cells are surrounded initially by normal tissue and later by tumor tissue. Hence, we asked if Ras exerts its oncogenic effects through the same set of effectors during different stages of tumorigenesis. We now show in human cells that the Ras effector pathways MAPK, RalGEF, and PI3K are required to initiate tumor growth. Conversely, activation of the PI3K/AKT pathway replaced Ras once tumors formed, although other effectors were still activated independently of Ras, presumably by factors provided upon the establishment of a tumor microenvironment. Thus, as tumorigenesis progresses the addiction of cancers to their initiating oncogene is reduced to, at least in the case of Ras, the PI3K/AKT pathway.
 ...
PMID:Reduction in the requirement of oncogenic Ras signaling to activation of PI3K/AKT pathway during tumor maintenance. 1628 46

Several recent reports have brought conclusive evidence that the tumor suppressor PTEN, once considered a strictly cytoplasmic protein, shuttles to the nuclear compartment, where it joins a variety of components of the same pathway it regulates in the cytoplasm, among which PI3K, PDK1 and AKT. In this review, we focus on the growing supporting evidence for an important physiological role of this nuclear pathway and on the role that alteration of this novel regulatory circuit may play during cell transformation.
 ...
PMID:Class reunion: PTEN joins the nuclear crew. 1628 86


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>