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)

Previous studies have demonstrated in hepatocytes that deoxycholic acid (DCA) promotes inactivation of protein tyrosine phosphatases (PTPases) and activation of ERBB1 and the extracellular-regulated kinase (ERK) 1/2 pathway. The present studies have determined the biochemical mechanism(s) through which these events occur. DCA and taurodeoxycholic acid (TDCA) (100 micromol/L) caused activation of ERBB1, insulin receptor, and the ERK1/2 and AKT pathways in primary rodent hepatocytes. DCA- and TDCA-induced receptor and signaling pathway activations were blocked by the reactive oxygen species (ROS) scavengers N-acetyl cysteine (NAC) and Trolox (TX), as well as by cyclosporin A (CsA) and bongkrekic acid (BKA). DCA activated the ERK1/2 pathway in HuH7 human hepatoma cells that was blocked by the incubation of cells with an ERBB1 inhibitor, NAC, TX, CsA, or BKA. DCA did not activate the ERK1/2 pathway in mitochondria-defective HuH7 Rho 0 cells. In HuH7 cells and primary hepatocytes, DCA enhanced the production of ROS, an effect that was abolished in Rho 0 cells and by prior incubation of cells with CsA or BKA. In hepatocytes and HuH7 cells, DCA inhibited PTPase activity. Incubation of hepatocytes with either CsA or BKA prevented DCA-induced inhibition of PTPase activity. Loss of mitochondrial function in Rho 0 cells also abolished the inhibitory effects of DCA on PTPase activity. In conclusion, DCA and TDCA cause ROS generation in hepatocytes that is dependent on metabolically active mitochondria. The generation of ROS is essential for PTPase inactivation, receptor tyrosine kinase activation, and enhanced signaling down the ERK1/2 and AKT pathways.
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PMID:Bile acids induce mitochondrial ROS, which promote activation of receptor tyrosine kinases and signaling pathways in rat hepatocytes. 1538 21

The Ret receptor tyrosine kinase mediates physiological signals of glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) and is essential for postnatal survival in mice. It is implicated in a number of human diseases and developmental abnormalities. Here, we describe our analyses of mice expressing a Ret mutant (RetDN) with diminished kinase activity that inhibits wild-type Ret activity, including its activation of AKT. All RetDN/+ mice died by 1 month of age and had distal intestinal aganglionosis reminiscent of Hirschsprung disease (HSCR) in humans. The RetDN/+ proximal small intestine also had severe hypoganglionosis and reduction in nerve fiber density, suggesting a potential mechanism for the continued gastric dysmotility in postsurgical HSCR patients. Unlike Ret-null mice, which have abnormalities in the parasympathetic and sympathetic nervous systems, the RetDN/+ mice only had defects in the parasympathetic nervous system. A small proportion of RetDN/+ mice had renal agenesis, and the remainder had hypoplastic kidneys and developed tubulocystic abnormalities postnatally. Postnatal analyses of the testes revealed a decreased number of germ cells, degenerating seminiferous tubules, maturation arrest and apoptosis, indicating a crucial role for Ret in early spermatogenesis.
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PMID:Mice expressing a dominant-negative Ret mutation phenocopy human Hirschsprung disease and delineate a direct role of Ret in spermatogenesis. 1546 71

Human Epidermal growth factor Receptors (HER) play an important role in cellular proliferation, and differentiation. Their overexpression in tumor tissues is often associated with a poor prognosis. Consequently, HER receptors are interesting therapeutic targets for cancer treatment. Two strategies are proposed. First, monoclonal antibodies can be used to inhibit the binding of one ligand to its receptor. The second approach is based upon the designing of tyrosine kinase inhibitors capable to bind into the phosphorylation site of the receptor. Consequently, both approaches block the signal transduction downstream. Resistance to anti receptor tyrosine kinase therapy can lead to enhanced morbidity associated with high therapeutic cost. Different mechanisms can be implicated. Non specific mechanisms include alterations of the signal transduction pathways (PI3K/AKT), recruitment of alternative receptor tyrosine kinase pathways (IGFR, VEGFR) and proteasome degradation inhibition. Other mechanisms are specific to HER and rely on inhibition of the binding of monoclonal antibodies (sialomucin-MUC4), heterodimerisation of HER, truncated soluble receptors intervention and mutated variants, as demonstrated very recently with EGF receptors, or genetic polymorphism. This paper reviews these different resistance mechanisms that have been identified in preclinical and clinical situations.
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PMID:[Targeting of membrane receptor tyrosine kinases: is there resistance in the HER?]. 1554 94

CI-1033 (Canertinib dihydrochloride) is an orally available pan-erbB receptor tyrosine kinase inhibitor that, unlike the majority of receptor inhibitors, effectively blocks signal transduction through all four members of the erbB family. In addition, it blocks the highly tumorigenic, constitutively activated variant of erbB-1, EGFRvIII, and inhibits downstream signaling through both the Ras/ MAP kinase, and PI-3 kinase/AKT pathways (Figure 1). CI-1033 is also unique in that it is an irreversible inhibitor; thereby providing prolonged suppression of erbB receptor-mediated signaling. Preclinical data show CI-1033 to be efficacious against a variety of human tumors in mouse xenograft models, including breast carcinomas.
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PMID:Early phase I data on an irreversible pan-erb inhibitor: CI-1033. What did we learn? 1568 9

In the last few years a body of knowledge has been generated on the molecular basis of gastrointestinal stromal tumors (GIST). These mesenchymal tumors are characterized by the expression of KIT protein and because they have an activating mutation in a class III receptor tyrosine kinase gene (KIT or PDGFRA). Several KIT-activating mutations, which are largely responsible for the development of this tumor, promote cell survival, proliferation, and migration through different pathways such as MAPK p42/44, AKT, S6K, STAT1, and STAT3. Likewise, gene-activating mutations in the gene PDGFRalpha which codes for the receptor tyrosine kinase, Platelet-derived growth factor receptor alpha have been identified in GIST lacking KIT mutations. This means that KIT and PDGFRalpha mutations appear to be alternative and mutually exclusive oncogenic pathways for GIST development. These tumors may occur anywhere along the gastrointestinal tract (GI). The most frequently involved sites are stomach and small intestine. They are typically chemo- and radioresistant. The discovery of a specific inhibitor of this tyrosine kinase, imatinib mesylate, has radically changed the prognosis of patients with unresectable disease. Only 4 yr after the first patient was successfully treated with imatinib, multiple phase II and III trials have been published and, currently, imatinib mesylate is the only effective systemic treatment available of these tumors. Response rates are approximately 70-90% with acceptable toxicity. GIST are the first model of a solid tumor efficiently treated with a molecular-targeted agent. This review summarizes the clinical and biological aspects of this unique neoplasm.
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PMID:A clinical and biological overview of gastrointestinal stromal tumors. 1575 Jan 90

11,11'-dideoxy-verticillin, a compound of the novel epidithiodioxopiprazine structural class, is isolated from the traditional Chinese medicinal herb Shiraia bambusicola. The present study demonstrated for the first time that 11,11'-dideoxy-verticillin has potent tyrosine kinase-inhibitory and anti-tumor activities. In the cell-free ELISA tyrosine kinase assay, 11,11'-dideoxy-verticillin significantly inhibited the activities of epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor-1/fms-like tyrosine kinase-1 (VEGFR-1/Flt-1) and human epidermal growth factor receptor-2 (HER2/ErbB-2), with relative specificity on EGFR and VEGFR-1 with IC50s of 0.136+/-0.109 and 1.645+/-0.885 nM, respectively. Exposure of 11,11'-dideoxy-verticillin for 1 h to EGFR-overexpressed MDA-MB-468 human breast carcinoma cells and HER2-overexpressed SK-OV-3 human ovarian adenocarcinoma cells resulted in obvious inhibition of EGF-induced phosphorylation of EGFR and HER2. In addition, 11,11'-dideoxy-verticillin also inhibited the EGF-induced phosphorylation of Erk1/2, but had no effect on the phosphorylation of AKT in both tumor cell lines. Moreover, 11,11'-dideoxy-verticillin has potent anti-tumor activity. In vitro cytotoxicity assay showed that 11,11'-dideoxy-verticillin potently inhibited the proliferation of four human breast tumor cell lines with an average IC50 value of 0.2 microM. In vivo, 11,11'-dideoxy-verticillin exhibited remarkable efficacy against mice sarcoma 180 and hepatoma 22 after daily i.p. administration of 0.5 or 0.75 mg/kg with inhibition rates ranging from 45.0 to 72.4%. Treated with 11,11'-dideoxy-verticillin at 0.5-2.0 microM for 36 h, MB-MB-468 cells exhibited significant apoptotic morphological changes. At low concentrations (0.0625-0.5 microM) for 24 h, 11,11'-dideoxy-verticillin induced a dose-dependent accumulation of MDA-MB-468 cells in the G2/M phase of the cell cycle. These results indicate that 11,11'-dideoxy-verticillin is a naturally derived growth factor receptor tyrosine kinase inhibitor with potent anti-tumor activity.
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PMID:11,11'-dideoxy-verticillin: a natural compound possessing growth factor receptor tyrosine kinase-inhibitory effect with anti-tumor activity. 1584 17

Hepatocellular carcinoma is often diagnosed at an advanced stage, when it is not amenable to curative therapies. There is no effective chemotherapy. Advances in cancer biology suggest that a limited number of pathways are responsible for initiating and maintaining dysregulated cell proliferation, which is the major cellular alteration responsible for the cancer phenotype. New treatments in development target several of these critical pathways, including agents targeting the receptor tyrosine kinase pathways, the Wnt/beta-catenin signaling pathway, the ubiquitin/proteasome degradation pathway, the epigenetic DNA methylation and histone deacetylation pathways, the PI3 kinase/AKT/mTOR pathway, angiogenic pathways, and telomerase. Several of these approaches hold significant promise for improving the long-term outcome of patients with advanced hepatocellular carcinoma. Because of the high prevalence of liver cirrhosis in hepatocellular carcinoma patients, these approaches must be coupled with new strategies for halting or reversing the progression of chronic liver disease.
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PMID:Hepatocellular carcinoma: molecular pathways and new therapeutic targets. 1591 49

Myoblast C2C12 cells cultured in the presence of FGF2 actively proliferate and showed a differentiation-defective phenotype compared with cells cultured in low serum or in the presence of insulin. These FGF2 effects are associated with sustained activation of p44/p42-MAPK and lack of activation of AKT. Here we demonstrate that Sprouty-2, a protein involved in the negative feedback of receptor tyrosine kinase signaling, when stably overexpressed in C2C12 cells and in the presence of FGF2 produces growth arrest (precluding the expression of PCNA and the phosphorylation of retinoblastoma and inducing the expression of p21(CIP)) and myogenesis (multinucleated myotubes formation, induction of creatine kinase and expression of myosin heavy chain protein). These events were accompanied by repression of p44/p42-MAPK and activation of AKT. When C2C12 cells were stably transfected with a Sprouty-2 (Y55F) mutant defective in inhibiting p44/p42-MAPK activation by FGF, myoblasts in the presence of FGF continue to grow and completely fail to form myotubes. This work is the first evidence of the contribution of sprouty genes to myogenic differentiation in the presence of FGF2.
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PMID:Sprouty-2 overexpression in C2C12 cells confers myogenic differentiation properties in the presence of FGF2. 1600 Mar 70

Insulin-like growth factor-I receptor (IGF-IR) plays an important role in tumor cell growth and survival. On ligand stimulation, IGF-IR, a receptor tyrosine kinase, phosphorylates tyrosine residues on two major substrates, IRS-1 and Shc, which subsequently signal through the Ras/mitogen-activated protein kinase and phosphatidylinositol 3-kinase/AKT pathways. Here, we describe the characterization of a fully human anti-IGF-IR monoclonal antibody 19D12 that inhibits IGF binding and autophosphorylation of both IGF-IR/IGF-IR homodimers and IGF-IR/insulin receptor heterodimers. 19D12 does not recognize insulin receptor homodimers. In addition to inhibiting IGF-IR autophosphorylation, 19D12 also inhibits IRS-1 phosphorylation and activation of the major downstream signaling molecules AKT and extracellular signal-regulated kinase 1/2. Furthermore, the antibody down-regulates the total IGF-IR protein level and can exhibit antibody-dependent cellular cytotoxicity activity against a non-small cell adenocarcinoma cell line in vitro in the presence of isolated human natural killer cells. 19D12 binds tightly to the receptor, with an affinity of 3.8 pmol/L as measured by KinExA. In cell culture, 19D12 inhibits proliferation and soft agar growth of various tumor cell lines. In vivo, 19D12 inhibits the tumor growth of a very aggressive human ovarian tumor xenograft model A2780. These data support the development of this anti-IGF-IR monoclonal antibody as a promising anticancer agent.
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PMID:Inhibition of insulin-like growth factor-I receptor (IGF-IR) signaling and tumor cell growth by a fully human neutralizing anti-IGF-IR antibody. 1609 37

Dominant-activating mutations in the RET (rearranged during transfection) proto-oncogene, a receptor tyrosine kinase, are causally associated with the development of multiple endocrine neoplasia type 2A (MEN2A) syndrome. Such oncogenic RET mutations induce its ligand-independent constitutive activation, but whether it spreads identical signaling to ligand-induced signaling is uncertain. To address this question, we designed a cellular model in which RET can be activated either by its natural ligand, or alternatively, by controlled dimerization of the protein that mimics MEN2A dimerization. We have shown that controlled dimerization leaves proximal RET signaling intact but impacts substantially on the tuning of the distal AKT kinase activation (delayed and sustained). In marked contrast, distal activation of ERK remained unaffected. We further demonstrated that specific temporal adjustment of ligand-induced AKT activation is dependent upon a lipid-based cholesterol-sensitive environment, and this control step is bypassed by MEN2A RET mutants. Therefore, these studies revealed that MEN2A mutations propagate previously unappreciated subtle differences in signaling pathways and unravel a role for lipid rafts in the temporal regulation of AKT activation.
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PMID:Inducible dimerization of RET reveals a specific AKT deregulation in oncogenic signaling. 1612 37


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